Pyrrolo-pyridine derivative compound, method for preparing same, and pharmaceutical composition containing same as active ingredient for prevention or treatment of protein kinase-related diseases

ABSTRACT

The present invention relates to a pyrrolo-pyridine derivative compound, a method for preparing the same, and a pharmaceutical composition containing the same as an active ingredient for the prevention or treatment of protein kinase-related diseases. A compound represented by chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, according to the present invention, has excellent inhibitory activity against various protein kinases including DYRK1A, and therefore, the pharmaceutical composition containing the same as an active ingredient can be favorably used in the treatment or prevention of protein kinase-related diseases. Particularly, the pharmaceutical composition can be effectively used in the prevention, treatment, or alleviation of Alzheimer&#39;s disease, dementia, or Alzheimer&#39;s dementia.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to a pyrrolo-pyridine derivative compound,a preparation method thereof, and a pharmaceutical composition for usein preventing or treating protein kinase related disease as an activeingredient.

2. Description of the Related Art

Protein kinase is an enzyme that catalyses the reaction to transfer theterminal phosphate group of adenosine triphosphate (ATP) to a specificresidue of protein (tyrosine, serine, threonine), and is involved insignals that regulate cell activation, growth, and differentiationaccording to extracellular mediators and environmental changes.

Inappropriately high protein kinase activity is directly or indirectlyinvolved in various diseases resulting from abnormal cellular functions.For example, mutation, over-expression or failure of appropriateregulatory mechanism of kinases involved in inappropriate enzymeactivity, or over-synthesis or deficiency of factors involved inupstream or downstream signal transduction of cytokines or kinases cancause disease. Therefore, selective inhibition of kinase activity can bea beneficial target for the development of new drugs for the treatmentof disease.

Brain cancer is a general term for primary brain cancer that occurs inthe brain tissue and the cerebral meninges surrounding the brain andsecondary brain cancer that has metastasized from the skull or otherparts of the body. Such brain cancer is distinguished from other cancersdeveloped in other organs in many aspects. First, cancers developed inlung, stomach and breast are limited in one or two types of cancer foreach organ and their properties are the same or similar. However, manydifferent types of cancers can be developed in the brain. For example,polymorphic glioblastoma, malignant glioma, lymphoma, blastoma, andmetastatic tumor can be developed in the brain.

Down syndrome is a disease caused by chromosome aberration, preciselycaused by trisomy of human chromosome 21, which is characterized by suchsymptoms as mental retardation, learning disorder and memory loss, earlyonset of Alzheimer's disease and cranial facial disorder. In particular,it is believed that the changes in the expression levels of such genesthat exist in a certain region called ‘Down syndrome critical regionDSCR)’ of human chromosome 21 cause Down syndrome. DYRK1A (dualspecificity tyrosine-phosphorylation-regulated kinase 1A) is a geneplaying an important role in the development and function of the nervecenter, and is also involved in phosphorylation of various proteins.This gene is particularly related to the symptoms like learningdisorder, memory loss, synaptic flexibility change, abnormal cell cycleand neuropathological symptoms similar to Alzheimer's dementia. So, itis necessary to understand biochemical, functional and molecularbiological effects of this protein for disclosing the pathogenesis ofDown syndrome related diseases and for developing therapeutic agents forDown syndrome related neurodefective.

Down syndrome is the most frequent chromosome abnormality syndrome,which is diagnosed one out of 700 new born babies. Down syndrome occursregardless of racial, environmental and socioeconomic differences. Theincidence is higher when the mother is over 35 years old. If the motheris over 40 years old, the frequency is 1 per 100 newborns. There is noway to prevent such genetic abnormality in modern medicine. It is onlypossible to determine whether the fetus has Down syndrome throughgenetic testing before birth.

Down syndrome patients display the following common physical features.Symptoms appear in all the body, which causes behavioral developmentdelay due to decreased brain function in children with Down syndrome.30˜40% of down syndrome patients are born with congenital heart diseasesuch as heart valve abnormalities and have a high incidence ofpneumonia, leukemia, bowel obstruction and enteritis due to decreasedimmunity. Most of symptoms can be treated or prevented due to theadvancement of medical technology so that the average life span of Downsyndrome patients is increasing to 50 years.

However, there have been no promising results produced so far regardingthe development of a therapeutic agent for cerebral nervous systemdepression and neurodegenerative symptoms, and Piracetam known toimprove cognitive ability has not been shown to be effective in childrenwith Down syndrome (Lobaugh, N. J. et al. (2001). “Piracetam therapydoes not enhance cognitive functioning in children with Down syndrome.”Arch Pediatr Adolesc Med 155: 442-448). Therefore, it is an urgentrequest to develop a novel therapeutic agent based on the disclosure ofthe fundamental cause mechanism of cerebral nervous system abnormalitiesin patients with Down syndrome.

On the other hand, Alzheimer's disease (AD) is a progressive diseasethat progresses to senile dementia. This disease can be divided intolate onset developed in aged people (over 65 years old) and early onsetdeveloped in people who are at the age between and 60. The pathologicalaspect is equal between these two types of disease above, but when thedisease is early onset, the symptoms are more severe and more prevalent.

All the developed medicinal products including those in the course ofstudy and development can delay the progress of Alzheimer's disease orare focused on the alleviation of the symptoms of Alzheimer's disease.In the recent two decades, drugs that can improve cognitive abilityespecially in patients in the early and intermediate stages of thedisease have been developed, and these drugs have been currently used asthe primary drugs to treat patients with Alzheimer's disease.

Particularly, acetylcholine esterase inhibitors (AchEI) andN-methyl-D-aspartate (NMDA) receptor antagonist are the examples ofthose drugs to treat AD, which are still aiming to alleviate thesymptoms of the disease, rather than targeting the disease pathway.

Tacrine is the first generation acetylcholine esterase inhibitor(AchEl), which was first approved for its antidementia action. It isknown that tacrine can delay the loss of cognitive function in about 30%of Alzheimer's disease patients in the early and intermediate stages byinhibiting the decomposition of acetylcholine generated in the brain.Even though tacrine has been known to delay the loss of cognitivefunction by inhibiting the decomposition of acetylcholine, the durationof action is short so that it has to be administered at least 4 times aday. In addition, it cannot prevent the degenerative changes of braincells, which are the fundamental problems of Alzheimer's disease, andeven worse it causes many liver related side effects, so that it ishardly used these days.

Donepezil, as the second generation cholinesterase inhibitor (ChEl)attracting our attention these days, was developed by Eisai Co., Japanand approved by FDA, USA, in the late 1996, and thus has been sold inover 30 countries since 1997. Donepezil can be taken once a day, and isable to inhibit selectively to reduce peripheral side effects.Rivastigmine is the drug developed by Novartis Co., USA and approved inDecember, 1997 in Switzerland and used in EU and South Americancountries. This drug is being prepared for approval in USA and Canada,and was introduced in Korea in September, 1997. Rivastigmine can betaken twice a day and has significantly reduced peripheral side effectsdue to its high specificity to the central nervous system. Rivastigmineis reported to have little hepatotoxicity since it is metabolized in thekidney. Metrifonate is undergoing a phase 3 clinical trial in dementiapatients and has been reported to have a long duration of action as anirreversible AChEI.

The pathological characteristics of Alzheimer's disease include amyloidplaque generated by the deposition of amyloid-beta peptide (AB) andneurofibrillary tangle formed by the hyper-phosphorylation of tauprotein which is functioning to stabilize microtubule.

Plaques are produced by the excessive accumulation of beta amyloid dueto the over-production or metabolic abnormalities in Alzheimer's diseasepatients. The loss of neurons can be caused by toxicity of beta amyloidand plaque, resulting in cognitive impairment and memory impairment.

In the course of developing an inhibitor of the expression of DYRK1A,which is a cause of various diseases including cancer, Down syndrome,diabetes, Alzheimer's disease and dementia, the present inventorsconfirmed that the pyrrolo-pyridine derivative compound of the presentinvention was able to inhibit the DYRK1A expression efficiently, leadingto the completion of the present invention.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a novelpyrrolo-pyridine derivative compound.

It is another object of the present invention to provide a preparationmethod of the pyrrolo-pyridine derivative compound.

It is another object of the present invention to provide apharmaceutical composition for preventing or treating a disease selectedfrom the group consisting of cancer, degenerative brain disease andmetabolic disease.

It is also an object of the present invention to provide a healthfunctional food composition for preventing or ameliorating a diseaseselected from the group consisting of cancer, degenerative brain diseaseand metabolic disease.

To achieve the above objects, the present invention provides a compoundrepresented by chemical formula 1 below, an optical isomer thereof or apharmaceutically acceptable salt thereof: [Chemical Formula 1]

In chemical formula 1,

R¹, X and Z are as defined in this specification.

The present invention also provides a preparation method of a compoundrepresented by chemical formula 1 comprising the following steps, asshown in reaction formula 1 below:

preparing a compound represented by chemical formula 4 by reacting acompound represented by chemical formula 2 with a compound representedby chemical formula 3 (step 1); and

preparing a compound represented by chemical formula 1 by reacting thecompound represented by chemical formula 4 prepared in step 1 above inthe presence of an acid (step 2):

In reaction formula 1,

R¹, X, X′, Z and PG are as defined in this specification.

The present invention also provides a pharmaceutical compositioncomprising a compound represented by chemical formula 1, an opticalisomer thereof or a pharmaceutically acceptable salt thereof as anactive ingredient for the prevention or treatment of protein kinaserelated disease.

The present invention also provides a pharmaceutical compositioncomprising a compound represented by chemical formula 1, an opticalisomer thereof or a pharmaceutically acceptable salt thereof as anactive ingredient for preventing or treating a disease selected from thegroup consisting of cancer, degenerative brain disease and metabolicdisease.

The present invention also provides a health functional food compositioncomprising a compound represented by chemical formula 1, an opticalisomer thereof or a pharmaceutically acceptable salt thereof as anactive ingredient for preventing or ameliorating a disease selected fromthe group consisting of cancer, degenerative brain disease and metabolicdisease.

The present invention also provides a method for preventing or treatinga disease selected from the group consisting of cancer, degenerativebrain disease and metabolic disease, which comprises the step ofadministering a pharmaceutical composition or a health functional foodcomposition comprising a compound represented by chemical formula 1 or apharmaceutically acceptable salt thereof as an active ingredient to asubject in need.

In addition, the present invention provides a use of the pharmaceuticalcomposition or the health functional food composition above comprising acompound represented by chemical formula 1 or a pharmaceuticallyacceptable salt thereof as an active ingredient for preventing ortreating a disease selected from the group consisting of cancer,degenerative brain disease and metabolic disease.

Advantageous Effect

The compound represented by chemical formula 1, the optical isomerthereof or the pharmaceutically acceptable salt thereof according to thepresent invention has an excellent activity of inhibiting variousprotein kinases including DYRK1A, so that a pharmaceutical compositioncomprising the same as an active ingredient can be effectively used forthe prevention or treatment of protein kinase related disease. Inparticular, it can be effectively used for the prevention, treatment oramelioration of Alzheimer's disease, dementia or Alzheimer's dementia.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is a graph illustrating the luciferase activity of DYRK1Aaffected by the compounds of Examples 53, 54, 55, 56 and 57.

FIG. 1b is a graph illustrating the luciferase activity of DYRK1Aaffected by the compounds of Examples 58, 59, 60, 61, 62, 63, 64, 65,66, 67 and 68.

FIG. 2a is a photograph illustrating the results of Tau, hnRNPA1 andGAPDH inhibition experiments for each concentration of the compound ofExample 57 in cells.

FIG. 2b is a graph illustrating the Tau inhibition rate at eachconcentration of the compound of Example 57 in cells.

FIG. 3a is a fluorescent confocal photomicrograph of the wild typeDrosophila embryo.

FIG. 3b is a fluorescent confocal photomicrograph of the Drosophilaembryo with minibrain overexpressing neurodevelopmental abnormality.

FIG. 3c is a fluorescent confocal photomicrograph of the Drosophilaembryo with minibrain overexpressing neurodevelopmental abnormalitywhich was born by the parents that had been treated with the compound ofExample 57 for 7 days before mating.

FIG. 4a is a photograph of wings of the control group and the Drosophilaover-expressing minibrain specifically in the wings.

FIG. 4b is a graph illustrating the inhibitory effect of the compoundsof Examples 58, 59, 60, 61, 62, 63, 64, 65, 66 and 67 of the presentinvention on the wing vein developmental abnormality.

FIG. 5a is an immunofluorescent staining confocal fluorescencephotomicrograph of the control group.

FIG. 5b is an immunofluorescent staining confocal fluorescencephotomicrograph of the mouse treated with harmine.

FIG. 5c is an immunofluorescent staining confocal fluorescencephotomicrograph of the mouse treated with the compound of Example 57.

FIG. 5d is a graph illustrating the cell number of each mouse model.

FIGS. 6a-6e present the results of the evaluation of Tau phosphorylationinhibitory activity of the compound in the Alzheimer's disease animalmodel. FIG. 6a : immunofluorescent staining confocal fluorescencephotomicrograph of the cerebral cortex of the Alzheimer's disease animalmodel treated with vehicle (untreated group) or the compound of Example57 (DAPI: immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), AT180: image obtained byimmunohistochemistry using AT180 antibody, Merge: image obtained byoverlapping DAPI and AT180 images, Enlarge: image obtained by enlargingAT180 image), FIG. 6b : graph illustrating the immunoreactivity of AT180in the cerebral cortex of the Alzheimer's disease animal model treatedwith vehicle (untreated group) or the compound of Example 57, FIG. 6c :immunofluorescent staining confocal fluorescence photomicrograph of thecerebral cortex of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57 (DAPI:immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), AT180: image obtained byimmunohistochemistry using AT180 antibody, Enlarge (CA1): enlarged imageof CA1 (cornus aminus, the region where the hippocampus begins andlong-term memory is formed) of the hippocampus of AT180 image, Enlarge(DG): enlarged image of DG (dentate gyrus, the region where thehippocampus ends and new memory is formed) of the hippocampus of AT180image, FIG. 6d : graph illustrating the immunoreactivity of AT180 in theCA1 (cornus aminus) of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57, FIG. 6e : graphillustrating the immunoreactivity of AT180 in the DG (dentate gyrus) ofthe Alzheimer's disease animal model treated with vehicle (untreatedgroup) or the compound of Example 57

FIGS. 7a-7e present the changes of DYRK1A protein by the compound of thepresent invention in the Alzheimer's disease animal model. FIG. 7a :immunofluorescent staining confocal fluorescence photomicrograph of thecerebral cortex of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57 (DAPI:immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), DYRK1A: image obtained byimmunohistochemistry using DYRK1A protein, Merge: image obtained byoverlapping DAPI and DYRK1A images, Enlarge: image obtained by enlargingDYRK1A image), FIG. 7b : graph illustrating the immunoreactivity ofDYRK1A in the cerebral cortex of the Alzheimer's disease animal modeltreated with vehicle (untreated group) or the compound of Example 57,FIG. 7c : immunofluorescent staining confocal fluorescencephotomicrograph of the cerebral cortex of the Alzheimer's disease animalmodel treated with vehicle (untreated group) or the compound of Example57 (DAPI: immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), DYRK1A: image obtained byimmunohistochemistry using DYRK1A protein, Enlarge (CA1): enlarged imageof CA1 (cornus aminus, the region where the hippocampus begins andlong-term memory is formed) of the hippocampus of DYRK1A image, Enlarge(DG): enlarged image of DG (dentate gyrus, the region where thehippocampus ends and new memory is formed) of the hippocampus of DYRK1Aimage, FIG. 7d : graph illustrating the immunoreactivity of DYRK1A inthe CA1 (cornus aminus) of the Alzheimer's disease animal model treatedwith vehicle (untreated group) or the compound of Example 57, FIG. 7e :graph illustrating the immunoreactivity of DYRK1A in the DG (dentategyrus) of the Alzheimer's disease animal model treated with vehicle(untreated group) or the compound of Example 57

FIGS. 8a-8d present the changes of amyloid plaque by the compound ofExample 57 in the Alzheimer's disease animal model. FIG. 8a :immunofluorescent staining confocal fluorescence photomicrograph of thecerebral cortex and the hippocampus of the Alzheimer's disease animalmodel treated with vehicle (untreated group) or the compound of Example57 (DAPI: immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), 4G8: image obtained byimmunohistochemistry using 4G8 antibody, Merge: image obtained byoverlapping DAPI and 4G8 images), FIG. 8b : graph illustrating thechanges in the number of amyloid plaque of 4G8 in the cerebral cortex ofthe Alzheimer's disease animal model treated with vehicle (untreatedgroup) or the compound of Example 57, FIG. 8c : graph illustrating thechanges in the number of amyloid plaque of 4G8 in the CA1 (cornusaminus) of the Alzheimer's disease animal model treated with vehicle(untreated group) or the compound of Example 57, FIG. 8d : graphillustrating the changes in the number of amyloid plaque of 4G8 in theDG (dentate gyrus) of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57

FIGS. 9a and 9b present the results of evaluating short term cognitiveimprovement effect through behavioral tests. FIG. 9a : schematic diagramof Y-maze to measure the short term memory of the brain, FIG. 9b : graphillustrating the behavioral changes of the mouse tested with Y-maze

FIGS. 10a-10c present the results of evaluating long term cognitiveimprovement effect through behavioral tests. FIG. 10a : schematicdiagram of novel object recognition test to measure the long term memoryof the brain and equation to calculate novel object preference, FIG. 10b: graph illustrating the object preference of the test mouse evaluatedby novel object recognition test, FIG. 10c : graph illustrating thenovel object preference of the test mouse evaluated by novel objectrecognition test

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the present invention is described in detail.

The present invention provides a compound represented by chemicalformula 1 below, an optical isomer thereof or a pharmaceuticallyacceptable salt thereof:

In chemical formula 1,

Z is cyano (—CN); or straight or branched C₁-C₃ alkyl substituted withone or more halogens;

X is —NR^(a)—, —O— or —S—, wherein R^(a) is hydrogen or straight orbranched C₁-C₁₀ alkyl, wherein, the alkyl can be substituted with one ormore substituents selected from the group consisting of —OH and C₁-C₃alkoxy;

R¹ is straight or branched C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl or C₆₋₁₄ aryl,wherein, the alkyl or cycloalkyl can be substituted with one or moresubstituents selected from the group consisting of —OH, and, straight orbranched C₁-C₃ alkyl and C₁-C₃ alkoxy, and the aryl can be substitutedwith one or more substituents selected from the group consisting ofstraight or branched C₁-C₃ alkyl and straight or branched C₁-C₃ alkoxy,nonsubstituted or substituted with one or more halogens;

or, R^(a) can form nonsubstituted or substituted 5-8 memberedheterocycloalkyl containing one or more heteroatoms selected from thegroup consisting of N, O and S along with R¹ and nitrogen atom to whichthey are attached, and the substituted heterocycloalkyl can besubstituted with one or more substituents selected from the groupconsisting of straight or branched C₁-C₆ alkyl and straight or branchedC₁-C₆ alkoxy; and

-   -   wherein, each R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are        independently one or more substituents selected from the group        consisting of hydrogen, halogen, straight or branched C₁-C₆        alkyl and straight or branched C₁-C₆ alkoxy;

R³, R⁵, R⁷ and R⁹ are independently hydrogen; straight or branched C₁-C₆alkyl or alkoxy; 3-8 membered heterocycloalkyl containing one or moreheteroatoms selected from the group consisting of N and O; or—(C═O)NR²⁶R²⁷, wherein R²⁶ and R²⁷ are independently hydrogen, straightor branched C₁-C₃ alkyl or 3-8 membered heterocycloalkyl containing oneor more heteroatoms selected from the group consisting of N and Osubstituted with 3-5 membered heterocycloalkyl containing one or moreoxygen atoms, or R²⁶ and R²⁷ form 3-8 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O along with nitrogen atom to which they are attached, wherein,the alkyl or heterocycloalkyl is substituted with one or moresubstituents selected from the group consisting of —CN, halogen,straight or branched C₁-C₃ alkyl, and, 3-6 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O nonsubstituted or substituted with one or more straight orbranched C₁-C₃ alkyl,

R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ are independently hydrogen orstraight or branched C₁-C₃ alkyl,

R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently hydrogen orstraight or branched C₁-C₃ alkyl, or, two of R¹², R¹³, R¹⁴, R¹⁵, R¹⁸,R¹⁹, R²⁰ and R²¹ bonded to the same carbon can form carbonyl along withthe carbon to which they are attached, and

R¹⁶, R²² and R²⁵ are independently hydrogen or straight or branchedC₁-C₃ alkyl, wherein the alkyl can be substituted with one or morehalogens.

In addition, Z is —CN or methyl substituted with one or more halogens;

X is —NR^(a)— or —O—, wherein R^(a) is hydrogen or straight or branchedC₁-C₆ alkyl, wherein, the alkyl can be substituted with one or moresubstituents selected from the group consisting of —OH and C₁-C₃ alkoxy;

R¹ is straight or branched C₁-C₆ alkyl, C₃-C₈ cycloalkyl or C₆₋₁₀ aryl,wherein, the alkyl can be substituted with one or more substituentsselected from the group consisting of —OH, methyl and methoxy, and thearyl can be substituted with one or more substituents selected from thegroup consisting of methyl and methoxy, nonsubstituted or substitutedwith one or more halogens;

or, R^(a) can form nonsubstituted or substituted 5-6 memberedheterocycloalkyl containing one or more heteroatoms selected from thegroup consisting of N, O and S along with R¹ and nitrogen atom to whichthey are attached, and the substituted heterocycloalkyl can besubstituted with one or more substituents selected from the groupconsisting of straight or branched C₁-C₃ alkyl and straight or branchedC₁-C₃ alkoxy; and

-   -   wherein, R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independently        one or more substituents selected from the group consisting of        hydrogen, halogen, straight or branched C₁-C₃ alkyl and straight        or branched C₁-C₃ alkoxy;

R³, R⁵, R⁷ and R⁹ are independently hydrogen, straight or branched C₁-C₃alkyl or alkoxy; morpholinyl, piperazinyl, piperidinyl or —(C═O)NR²⁶R²⁷, wherein R²⁶ and R²⁷ are independently hydrogen, methyl,morpholinyl, piperazinyl or piperidinyl, or R²⁶ and R²⁷ formmorpholinyl, piperazinyl or piperidinyl along with nitrogen atom towhich they are attached, wherein, the C₁-C₃ alkyl, morpholinyl,piperazinyl or piperidinyl can be substituted with one or moresubstituents selected from the group consisting of —CN, fluoro,oxetanyl, morpholinyl, piperazinyl, and, nonsubstituted or substitutedwith methyl piperidinyl,

R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ are independently hydrogen,methyl or ethyl,

R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently hydrogen,methyl or ethyl, or, two of R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹bonded to the same carbon can form carbonyl along with the carbon towhich they are attached, and

R¹⁶, R²² and R²⁵ are independently hydrogen or, methyl nonsubstituted orsubstituted with one or more halogens or ethyl nonsubstituted orsubstituted with one or more halogens.

Further, Z is —CN or —CF₃;

X is —NR^(a)— or —O—, wherein R^(a) is hydrogen or methyl;

R¹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl,

1-methylcyclopropyl, tetrahydropyranyl, tetrahydrofuranyl, or, phenylsubstituted with one or more CF₃;

or, R^(a) can form morpholinyl along with R¹ and nitrogen atom to whichthey are attached; and

wherein, R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independently one ormore substituents selected from the group consisting of hydrogen,chloro, fluoro, methyl and methoxy;

R³ and R⁷ are independently methoxy,

R⁵ and R⁹ are independently methyl, isopropyl,

R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ are independently hydrogen ormethyl,

R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently hydrogen ormethyl, or, two of R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ bonded tothe same carbon can form carbonyl along with the carbon to which theyare attached, and

R¹⁶, R²² and R²⁵ are independently hydrogen, or, methyl nonsubstitutedor substituted with one or more halogens.

Furthermore, Z is —CN or —CF₃;

X is —NR^(a)— or —O—, wherein R^(a) is hydrogen or methyl;

R¹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl,

1-methylcyclopropyl, tetrahydropyran-4-yl or tetrahydrofuran-3-yl, or,

or, R^(a) can form morpholinyl along with R¹ and nitrogen atom to whichthey are attached; and

Further, the compound represented by chemical formula 1 above can be anyone selected from the group consisting of the following compounds.

(1)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(2)4-(ethylamino)-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(3)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(4)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(5)4-((2-methoxyethyl)amino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(6)4-((2-methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(7)4-((2-methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(8)4-(ethylamino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(9)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(10)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(11)4-(propylamino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(12)6-((1-methyl-1H-pyrazol-4-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(13)6-((1-methyl-1H-pyrazol-3-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(14)4-(ethylamino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(15)4-(ethylamino)-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(16)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(17)6-((5-fluoro-2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(18)4-(ethylamino)-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(19)6-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(20)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(21)6-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(22)(R)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(23)(S)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(24)6-((4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-2-methoxyphenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(25)6-((4-(4,4-difluoropiperidine-1-carbonyl)-2-methoxyphenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(26)(R)-4-(ethylamino)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(27)(S)-4-(ethylamino)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(28)6-((4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-2-methoxyphenyl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(29)6-((4-(4,4-difluoropiperidine-1-carbonyl)-2-methoxyphenyl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(30)6-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(31)6-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(32)4-(ethylamino)-6-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(33)4-(ethylamino)-6-((1-isopropyl-5-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(34)6-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(35)6-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(36)6-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(37)6-((1-isopropyl-5-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(38)6-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(39)6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(40)4-(ethylamino)-6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(41)6-((5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(42)6-((5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; (43)(R)-4-(ethylamino)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(44)(R)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(45)3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone; (46)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone; (47)4-methoxy-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(48)4-methoxy-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(49)4-ethoxy-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(50)4-ethoxy-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(51)(R)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-4-(1-methylcyclopropoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(52)6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-4-(1-methylcyclopropoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(53)N⁴-ethyl-3-(trifluoromethyl)-N⁶-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(54)N⁴-ethyl-N⁶-(1-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(55)N⁴-ethyl-N⁶-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(56)(4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(morpholino)methanone; (57)(4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone; (58)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone; (59)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-morpholinopiperidin-1-yl)methanone; (60)(2-fluoro-5-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone; (61)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone; (62)N⁶-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N⁴-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(63)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone; (64)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6yl)amino)phenyl)(morpholino)methanone; (65)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-morpholinopiperidin-1-yl)methanone; (66)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)-methanone; (67)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)piperidin-1-yl)methanone; (68)N⁶-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(2-methoxyethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(69)N⁶-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N⁴-ethyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(70)(4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone; (71)4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-5methoxy-N-(1-(oxetanepiperidin-4-yl)benzamide;(72)4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzylamide;(73)2-fluoro-5-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)(1-methylpiperidin-4-yl)benzamide; (74)4-((4-(ethylamino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-N-(1-isopropylpiperidin-4-yl)-5-methoxybenzamide;(75) (R)-(2,4-dimethylpiperazin-1-yl)(2-fluoro-5-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino) phenyl) methanone; (76)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino) methanone; (77)N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6-amine;(78)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(79)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-methoxyethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(80)1-(6-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one;(81)N4-ethyl-N6-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(82)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone; (83)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl) (4-(4-methylpiperazin-1-yl) piperidin-1-yl)methanone; (84)(3-methoxy-4-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenyl)(morpholino)methanone; (85)(3-methoxy-4-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenyl)(4-morpholinopiperidin-1-yl)methanone; (86)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)-N4-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(87)(3-methoxy-4-((4-methoxyethyl)(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone; (88)(3-methoxy-4-((4-methoxyethyl)(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl) ((4-morpholinopiperidin-1-yl) methanone; (89)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methoxyethyl)-N4-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(90)(4-(4-(isopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone; (91)(R)-(4-((4-((1-hydroxy-3-methylbutan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone; (92)(R)-(4-((4-((1-hydroxy-3-methylbutan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]amino)-3-methoxyphenyl)(morpholino)methanone; (93)(S)-(4-((4-(2-butylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)-methanone; (94)(4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone; (95)(4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(morpholino) methanone; (96)5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-methoxy-2-methylisoindolin-1-one; (97)7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[1,4]oxazin-3(4H)-1-one;(98)6-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-5-methoxy-2-methylisoindolin-1-one; (99)4-(ethylamino)-6-((6-methoxy-2-methyl-3-oxoisoindol-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(100) 6-((2(2-cyanopropan-2-yl)-4-methylthiazol-5-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile; (101)(6-chloro-5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-methylisoindolin-1-one; (102)5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-methylisoindolin-1-one;(103)4-(ethylamino)-6-((2-methyl-1-oxoisoindol-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(104)6-((6-chloro-2-methyl-1-oxoisoindolin-5-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;and (105)4-(ethylamino)-6-((6-methoxy-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.

The compound represented by chemical formula 1 of the present inventioncan be used as a form of a pharmaceutically acceptable salt, in whichthe salt is preferably acid addition salt formed by pharmaceuticallyacceptable free acids. The acid addition salt herein can be obtainedfrom inorganic acids such as hydrochloric acid, nitric acid, phosphoricacid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid,and phosphorous acid; non-toxic organic acids such as aliphaticmono/dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate,alkandioate, aromatic acids, and aliphatic/aromatic sulfonic acids; ororganic acids such as acetic acid, benzoic acid, citric acid, lacticacid, maleic acid, gluconic acid, methanesulfonic acid,4-toluenesulfonic acid, tartaric acid, and fumaric acid. Thepharmaceutically non-toxic salts are exemplified by sulfate,pyrosulfate, bisulfate, sulphite, bisulphite, nitrate, phosphate,monohydrogen phosphate, dihydrogen phosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutylate, caprate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,cabacate, fumarate, maliate, butyne-1,4-dioate, hexane-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, terephthalate,benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate,citrate, lactate, hydroxybutylate, glycolate, malate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, and mandelate.

The acid addition salt in this invention can be prepared by theconventional method known to those in the art. For example, thederivative represented by chemical formula 1 is dissolved in an organicsolvent such as methanol, ethanol, acetone, dichloromethane, andacetonitrile, to which organic acid or inorganic acid is added to induceprecipitation. Then, the precipitate is filtered and dried to give thesalt. Or the solvent and the excessive acid are distillated underreduced pressure, and dried to give the salt. Or the precipitate iscrystallized in an organic solvent to give the same.

A pharmaceutically acceptable metal salt can be prepared by using abase. Alkali metal or alkali earth metal salt is obtained by thefollowing processes: dissolving the compound in excessive alkali metalhydroxide or alkali earth metal hydroxide solution; filteringnon-soluble compound salt; evaporating the remaining solution and dryingthereof. At this time, the metal salt is preferably prepared in thepharmaceutically suitable form of sodium, potassium, or calcium salt.And the corresponding silver salt is prepared by the reaction of alkalimetal or alkali earth metal salt with proper silver salt (ex; silvernitrate).

The compound represented by chemical formula 1 according to the presentinvention, an optical isomer thereof or a pharmaceutically acceptablesalt thereof is excellent in inhibiting DYRK1A kinase activity and hasalso been confirmed to have excellent DYRK1A kinase inhibitory activityat the cellular level through DYRK1A high dependent calcienurin/NFATsignaling experiment. In addition, the compound of the present inventionis excellent in inhibiting phosphorylation of Tau, known as an importantfactor of Down syndrome, and in inhibiting DYRK1A in vivo, confirmed byin vivo experiments. Therefore, the compound represented by chemicalformula 1 according to the present invention, an optical isomer thereofor a pharmaceutically acceptable salt thereof can be effectively usedfor the treatment or prevention of DYRK1A related disease (seeExperimental Examples 1˜5).

The compound represented by chemical formula 1 according to the presentinvention, an optical isomer thereof or a pharmaceutically acceptablesalt thereof has the activity of inhibiting not only DYRK1A kinase butalso other kinases such as ALK, ALK (C1156Y), ALK (L1196M), CAMK1B,CAMK1D, CHEK2, CLK1, CLK2, CLK3, CLK4, CSNK1A1, CSNK1A1L, CSNK1D,CSNK1E, CSNK1G2, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK2, DYRK1A, DYRKIB,DYRK2, ERK5, ERN1, GAK, HASPIN, INSRR, JNK1, JNK2, JNK3, KIT (V559D),LATS2, LRRK2, LRRK2 (G2019S), LTK, MAPKAPK2, MEK1, MEK2, MEK3, MEK4,MYLK, NIK, PHKG1, PHKG2, PIP5K2C, PRKD1, PRKD2, PRKD3, RIPK5, ROCK1,ROCK2, RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.2-C-terminal),RSK3 (Kin.Dom.2-C-terminal), STK33, STK39, TSSK1B, TSSK3, TTK or YSK4,so that it can be effectively used for the treatment of ALK, ALK(C1156Y), ALK (L1196M), CAMK1B, CAMK1D, CHEK2, CLK1, CLK2, CLK3, CLK4,CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G2, CSNK1G3, DAPK1, DAPK2,DAPK3, DRAK2, DYRK1A, DYRKIB, DYRK2, ERK5, ERN1, GAK, HASPIN, INSRR,JNK1, JNK2, JNK3, KIT (V559D), LATS2, LRRK2, LRRK2 (G2019S), LTK,MAPKAPK2, MEK1, MEK2, MEK3, MEK4, MYLK, NIK, PHKG1, PHKG2, PIP5K2C,PRKD1, PRKD2, PRKD3, RIPK5, ROCK1, ROCK2, RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.2-C-terminal), RSK3(Kin.Dom.2-C-terminal), STK33, STK39, TSSK1B, TSSK3, TTK or YSK4 relateddisease as well (see Experimental Example 6).

The compound represented by chemical formula 1 of the present inventiondisplays an effect of alleviating Alzheimer's disease, so that it can beeffectively used for the treatment of Alzheimer's dementia (seeExperimental Examples 7˜9).

The compound represented by chemical formula 1 of the present inventioncan improve the short term cognitive decline caused by Alzheimer'sdisease, so that it can be effectively used for the treatment ofAlzheimer's dementia (see Experimental Example 10).

The compound represented by chemical formula 1 of the present inventioncan also improve the long term cognitive decline caused by Alzheimer'sdisease, so that it can be effectively used for the treatment ofAlzheimer's dementia (see Experimental Example 11).

In addition, the present invention provides a preparation method of acompound represented by chemical formula 1 comprising the followingsteps, as shown in reaction formula 1 below:

preparing a compound represented by chemical formula 4 by reacting acompound represented by chemical formula 2 with a compound representedby chemical formula 3 (step 1); and

preparing a compound represented by chemical formula 1 by reacting thecompound represented by chemical formula 4 prepared in step 1 above inthe presence of an acid (step 2):

In reaction formula 1, X, Z, R¹ and

are as defined in chemical formula 1 above;

X′ is halogen; and

PG is (2-(trimethylsilyl)methoxy)methyl (SEM), t-butyloxycarbonyl (BOC),carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac),benzoyl (Bz), benzyl (Bn), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl(PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc),2-trimethylsilylethoxycarbonyl (Teoc), aryloxycarbonyl (Alloc) orp-methoxybenzyl (PMB).

Hereinafter, the preparation method according to the present inventionis described in more detail.

In the preparation method of the present invention, step 1 is to preparea compound represented by chemical formula 4 by reacting a compoundrepresented by formula 2 with a compound represented by chemical formula3.

As a preferable example of step 1, a compound represented by chemicalformula 2 and a compound represented by chemical formula 3 are dissolvedin a solvent in the presence of a base and then gas is eliminated byultrasonic treatment. A palladium catalyst and Xphos are added to theprepared reaction mixture at 100° C., followed by reaction for 2 hours.

At this time, the base herein can be selected from the group consistingof such inorganic bases as cesium carbonate, sodium t-butoxide,potassium t-butoxide, sodium hydroxide, sodium carbonate, potassiumcarbonate and sodium hydride; and such organic bases asN,N-diaisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene(DBU), pyridine and triethylamine. The selected base can be used in anequivalent amount or excess amount, alone or in combination. Herein, itis preferable to use potassium carbonate.

The palladium catalyst can be exemplified bytris(dibenzylideneacetone)palladium (Pd₂(dba)₃),tetrakis(triphenylphosphine)palladium (Pd(Ph₃P)₄), palladium charcoal(Pd—C), bis(triphenylphosphine)palladium dichloride (PdCl₂ (PPh₃)₂),[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl₂(dppf)),allylpalladium chloride dimer ([PdCl(allyl)]₂), palladium acetate(Pd(OAc)₂) and palladium chloride (PdCl₂), among whichtris(dibenzylideneacetone)palladium (Pd₂(dba)₃) is preferred.

The reaction solvent usable herein is exemplified by toluene,dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide(DMSO), methylenechloride, dichloroethane, water, ethylacetate,acetonitrile; lower alcohols including isopropanol, methanol, ethanol,propanol and butanol; and ether solvents including tetrahydrofuran(THF), dioxane, ethylether and 1,2-dimethoxyethane, which can be usedindependently or together, and sec-butanol is more preferred herein.

After the reaction, the reaction mixture can be filtered with afiltration membrane and washed with an organic solvent. The solidcompound 4 obtained after the concentration of the filtrate can be usedin the next step without further purification.

At this time, the reaction solvent is exemplified by toluene,dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide(DMSO), methylenechloride, dichloroethane, water, ethylacetate,acetonitrile; lower alcohols including isopropanol, methanol, ethanol,propanol and butanol; and ether solvents including tetrahydrofuran(THF), dioxane, ethylether and 1,2-dimethoxyethane, which can be usedindependently or together, and EtOAc (ethyl acetate) and MeOH (methanol)are more preferred herein.

Next step (step 2) is to prepare a compound represented by chemicalformula 1 by reacting the compound represented by chemical formula 4prepared in step 1 above in the presence of an acid.

As a preferable example of step 2, a compound represented by chemicalformula 3 was dissolved in dichloromethane, to which TFA(trifluoroacetic acid) was added at room temperature. After 4 hours ofthe reaction, the solvent was removed. Then, the concentrated mixturewas dissolved in an organic solvent again. A base was added thereto atroom temperature, followed by reaction for 14 hours.

At this time, the base herein can be selected from the group consistingof such inorganic bases as cesium carbonate, sodium t-butoxide,potassium t-butoxide, sodium hydroxide, sodium carbonate, potassiumcarbonate and sodium hydride; and such organic bases asN,N-diaisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]-7-undecene(DBU), pyridine and triethylamine. The selected base can be used in anequivalent amount or excess amount, alone or in combination. Herein, itis preferable to use saturated potassium carbonate.

Upon completion of the reaction, the reaction product was diluted inEtOAc (ethyl acetate), followed by washing with water and brinestepwise. The organic layer was dried over MgSO₄ (magnesium sulfate).Then, the reaction mixture was purified by prep-HPLC and as a result asolid compound 1 was obtained.

The present invention also provides a pharmaceutical compositioncomprising a compound represented by chemical formula 1, an opticalisomer thereof or a pharmaceutically acceptable salt thereof as anactive ingredient for preventing or treating a disease selected from thegroup consisting of cancer, degenerative brain disease and metabolicdisease.

The compound represented by chemical formula 1 above can inhibit theprotein kinase activity.

At this time, the protein kinase can be ALK, ALK (C1156Y), ALK (L1196M),CAMK1B, CAMK1D, CHEK2, CLK1, CLK2, CLK3, CLK4, CSNK1A1, CSNK1A1L,CSNK1D, CSNK1E, CSNK1G2, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK2, DYRK1A,DYRKIB, DYRK2, ERK5, ERN1, GAK, HASPIN, INSRR, JNK1, JNK2, JNK3, KIT(V559D), LATS2, LRRK2, LRRK2 (G2019S), LTK, MAPKAPK2, MEK1, MEK2, MEK3,MEK4, MYLK, NIK, PHKG1, PHKG2, PIP5K2C, PRKD1, PRKD2, PRKD3, RIPK5,ROCK1, ROCK2, RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.2-C-terminal), STK33, STK39,TSSK1B, TSSK3, TTK or YSK4.

The degenerative brain disease herein can be Alzheimer's disease, Downsyndrome, Parkinson's disease, Lou Gehrig's disease, dementia,Huntington's disease, multiple sclerosis, proximal lateral sclerosis,apoplexy, stroke or mild cognitive impairment.

The said dementia can be Alzheimer's dementia, cerebrovascular dementia,dementia caused by head injury, multi-infarct dementia,Alzheimer's/multi-infarction dementia or alcoholic dementia.

The metabolic disease herein can be diabetes, hypoglycemia,hypercholesterolemia, hyperlipidemia, hemochromatosis, amyloidosis orporphyria.

The cancer can be brain cancer, brain tumor, benign astrocytoma,malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma,oligodendroglioma, intracranial carcinoma, ependymoma, brainstem tumor,head and neck tumor, larynx cancer, oropharyngeal cancer, nasalcavity/paranasal sinus cancer, nasopharyngeal cancer, salivary glandcancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracictumor, small cell lung cancer, non-small cell lung cancer, thymuscancer, mediastinal tumor, esophageal cancer, breast cancer, male breastcancer, abdominal tumor, stomach cancer, liver cancer, gallbladdercancer, biliary cancer, pancreatic cancer, small bowel cancer, coloncancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, malegenital tumor, penile cancer, prostate cancer, female genital tumor,cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma,vaginal cancer, female external genital cell cancer, female urethralcancer or skin cancer. The degenerative brain disease can be Alzheimer'sdisease, Down syndrome, Parkinson's disease, Lou Gehrig's disease,dementia, Huntington's disease, multiple sclerosis, proximal lateralsclerosis, apoplexy, stroke or mild cognitive impairment. In addition,the metabolic disease herein can be diabetes, hypoglycemia,hypercholesterolemia, hyperlipidemia, hemochromatosis, amyloidosis orporphyria.

The compound represented by chemical formula 1 or the pharmaceuticallyacceptable salt thereof included in the pharmaceutical composition ofthe present invention can be administered orally or parenterally and beused in general forms of pharmaceutical formulation. That is, thecomposition of the present invention can be prepared for oral orparenteral administration by mixing with generally used diluents orexcipients such as fillers, extenders, binders, wetting agents,disintegrating agents and surfactants.

The formulations for oral administration are exemplified by tablets,pills, hard/soft capsules, solutions, suspensions, emulsions, syrups,granules, elixirs, and troches, etc. These formulations can includediluents (for example, lactose, dextrose, sucrose, mannitol, sorbitol,cellulose, and/or glycine) and lubricants (for example, silica, talc,stearate and its magnesium or calcium salt, and/or polyethylene glycol)in addition to the active ingredient. Tablets can include binding agentssuch as magnesium aluminum silicate, starch paste, gelatin,methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrolidone, and if necessary disintegrating agents such asstarch, agarose, alginic acid or its sodium salt or azeotropic mixturesand/or absorbents, coloring agents, flavours, and sweeteners can beadditionally included thereto.

The pharmaceutical composition comprising the compound represented bychemical formula 1 or the pharmaceutically acceptable salt thereof as anactive ingredient can be administered by parenterally and the parenteraladministration includes subcutaneous injection, intravenous injection,intramuscular injection, or intrathoracic injection.

To prepare the compound represented by chemical formula 1 or thepharmaceutically acceptable salt thereof as a formulation for parenteraladministration, the compound represented by chemical formula 1 or thepharmaceutically acceptable salt thereof is mixed with a stabilizer or abuffering agent in water to produce a solution or suspension, which isthen formulated as ampoules or vials. The composition herein can besterilized and additionally contains preservatives, stabilizers,wettable powders or emulsifiers, salts and/or buffers for the regulationof osmotic pressure, and other therapeutically useful materials, and thecomposition can be formulated by the conventional mixing, granulating orcoating method.

The effective dosage of the pharmaceutical composition comprising thecompound represented by chemical formula 1 or the pharmaceuticallyacceptable salt thereof as an active ingredient can be determinedaccording to age, weight, gender, administration method, healthcondition, and severity of disease. The dosage is generally 0.1˜1000mg/day, and preferably 1˜500 mg/day based on an adult patient weighing70 kg, which can be administered once or several times a day atintervals of a certain time depending on the judgment of a doctor or apharmacist.

The pharmaceutical composition comprising the compound represented bychemical formula 1 or the pharmaceutically acceptable salt thereof as anactive ingredient can be administered alone or together with surgicaloperation, hormone therapy, chemo-therapy and biological regulators toprevent and treat DYRK1A related disease.

The compound represented by chemical formula 1 of the present invention,the optical isomer thereof or the pharmaceutically acceptable saltthereof was confirmed to have excellent activity to inhibit DYRK1Akinase in Experimental Examples 1 and 2. In addition, the compoundrepresented by chemical formula 1 of the present invention, the opticalisomer thereof or the pharmaceutically acceptable salt thereof wasconfirmed to have excellent activity to inhibit DYRK1A phosphorylationat the cellular level in Experimental Example 3. It was also confirmedin Experimental Example 4 that the compound represented by chemicalformula 1 of the present invention, the optical isomer thereof or thepharmaceutically acceptable salt thereof was excellent in inhibitingphosphorylation of Tau, an important factor of Down syndrome. Further,it was also confirmed in Experimental Example 5 that the compoundrepresented by chemical formula 1 of the present invention, the opticalisomer thereof or the pharmaceutically acceptable salt thereof hadDYRK1A kinase activity inhibiting effect in vivo.

The compound represented by chemical formula 1 of the present invention,the optical isomer thereof or the pharmaceutically acceptable saltthereof was confirmed to have excellent activity to inhibit Tauphosphorylation in the Alzheimer's disease animal model in ExperimentalExample 7. It was also confirmed in Experimental Example 8 that thecompound represented by chemical formula 1 of the present invention, theoptical isomer thereof or the pharmaceutically acceptable salt thereofwas excellent in inhibiting DYRK1A protein activity. In ExperimentalExample 9, the compound represented by chemical formula 1 of the presentinvention, the optical isomer thereof or the pharmaceutically acceptablesalt thereof was confirmed to reduce amyloid plaque, one of causes ofAlzheimer's disease. In Experimental Example 10, the compoundrepresented by chemical formula 1 of the present invention, the opticalisomer thereof or the pharmaceutically acceptable salt thereof wasconfirmed to improve the short term cognitive decline caused byAlzheimer's disease, and also confirmed to improve the long termcognitive decline caused by Alzheimer's disease in Experimental Example11.

Therefore, a pharmaceutical composition and a health functional foodcomposition comprising the compound represented by chemical formula 1 ofthe present invention, the optical isomer thereof or thepharmaceutically acceptable salt thereof can be effectively used for thetreatment or prevention of DYRK1A related disease. In particular, theycan be effectively used for the prevention, treatment or amelioration ofAlzheimer's disease, dementia or Alzheimer's dementia.

The present invention also provides a health functional food compositioncomprising a compound represented by chemical formula 1, an opticalisomer thereof or a pharmaceutically acceptable salt thereof as anactive ingredient for preventing or ameliorating a disease selected fromthe group consisting of cancer, degenerative brain disease and metabolicdisease.

The compound represented by chemical formula 1 above can inhibit theprotein kinase activity.

At this time, the protein kinase can be ALK, ALK (C1156Y), ALK (L1196M),CAMK1B, CAMK1D, CHEK2, CLK1, CLK2, CLK3, CLK4, CSNK1A1, CSNK1A1L,CSNK1D, CSNK1E, CSNK1G2, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK2, DYRK1A,DYRKiB, DYRK2, ERK5, ERN1, GAK, HASPIN, INSRR, JNK1, JNK2, JNK3, KIT(V559D), LATS2, LRRK2, LRRK2 (G2019S), LTK, MAPKAPK2, MEK1, MEK2, MEK3,MEK4, MYLK, NIK, PHKG1, PHKG2, PIP5K2C, PRKD1, PRKD2, PRKD3, RIPK5,ROCK1, ROCK2, RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.2-C-terminal), STK33, STK39,TSSK1B, TSSK3, TTK or YSK4.

The degenerative brain disease herein can be Alzheimer's disease, Downsyndrome, Parkinson's disease, Lou Gehrig's disease, dementia,Huntington's disease, multiple sclerosis, proximal lateral sclerosis,apoplexy, stroke or mild cognitive impairment.

The said dementia can be Alzheimer's dementia, cerebrovascular dementia,dementia caused by head injury, multi-infarct dementia,Alzheimer's/multi-infarction dementia or alcoholic dementia.

The metabolic disease herein can be diabetes, hypoglycemia,hypercholesterolemia, hyperlipidemia, hemochromatosis, amyloidosis orporphyria.

The cancer can be brain cancer, brain tumor, benign astrocytoma,malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma,oligodendroglioma, intracranial carcinoma, ependymoma, brainstem tumor,head and neck tumor, larynx cancer, oropharyngeal cancer, nasalcavity/paranasal sinus cancer, nasopharyngeal cancer, salivary glandcancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracictumor, small cell lung cancer, non-small cell lung cancer, thymuscancer, mediastinal tumor, esophageal cancer, breast cancer, male breastcancer, abdominal tumor, stomach cancer, liver cancer, gallbladdercancer, biliary cancer, pancreatic cancer, small bowel cancer, coloncancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, malegenital tumor, penile cancer, prostate cancer, female genital tumor,cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma,vaginal cancer, female external genital cell cancer, female urethralcancer or skin cancer. The degenerative brain disease can be Alzheimer'sdisease, Down syndrome, Parkinson's disease, Lou Gehrig's disease,dementia, Huntington's disease, multiple sclerosis, proximal lateralsclerosis, apoplexy, stroke or mild cognitive impairment. In addition,the metabolic disease herein can be diabetes, hypoglycemia,hypercholesterolemia, hyperlipidemia, hemochromatosis, amyloidosis orporphyria.

The compound represented by chemical formula 1 of the present inventioncan be used as a food additive. In that case, the compound representedby chemical formula 1 of the present invention can be added as it is oras mixed with other food components according to the conventionalmethod. The mixing ratio of active ingredients can be regulatedaccording to the purpose of use (prevention or amelioration). Ingeneral, the compound of the present invention is preferably added tofood or beverages by 0.1˜90 weight part for the total weight of the foodor beverages. However, if long term administration is required forhealth and hygiene or regulating health condition, the content can belower than the above but higher content can be accepted as well sincethe compound of the present invention has been proved to be very safe.

The health beverage composition of the present invention canadditionally include various flavors or natural carbohydrates, etc, likeother beverages. The natural carbohydrates above can be one ofmonosaccharides such as glucose and fructose; disaccharides such asmaltose and sucrose; polysaccharides such as dextrin and cyclodextrin,and sugar alcohols such as xilytole, sorbitol and erythritol. Besides,natural sweetening agents (thaumatin, stevia extract, for examplerebaudioside A, glycyrrhizin, etc.) and synthetic sweetening agents(saccharin, aspartame, etc.) can be included as a sweetening agent. Thecontent of the natural carbohydrate is preferably 1˜20 g and morepreferably 5˜12 g in 100 g of the composition of the invention.

In addition to the ingredients mentioned above, the compound representedby chemical formula 1 of the present invention can include in variety ofnutrients, vitamins, minerals (electrolytes), flavors including naturalflavors and synthetic flavors, coloring agents and extenders (cheese,chocolate, etc.), pectic acid and its salts, alginic acid and its salts,organic acid, protective colloidal viscosifiers, pH regulators,stabilizers, antiseptics, glycerin, alcohols, carbonators which used tobe added to soda, etc. The compound represented by chemical formula 1 ofthe present invention can also include natural fruit juice, fruitbeverages and fruit flesh addable to vegetable beverages.

The present invention also provides a method for preventing or treatinga disease selected from the group consisting of cancer, degenerativebrain disease and metabolic disease, which comprises the step ofadministering a pharmaceutical composition or a health functional foodcomposition comprising a compound represented by chemical formula 1 or apharmaceutically acceptable salt thereof as an active ingredient to asubject in need.

In addition, the present invention provides a use of the pharmaceuticalcomposition or the health functional food composition above comprising acompound represented by chemical formula 1 or a pharmaceuticallyacceptable salt thereof as an active ingredient for preventing ortreating a disease selected from the group consisting of cancer,degenerative brain disease and metabolic disease.

Practical and presently preferred embodiments of the present inventionare illustrative as shown in the following Examples.

However, it will be appreciated that those skilled in the art, onconsideration of this disclosure, may make modifications andimprovements within the spirit and scope of the present invention.

<Preparative Example 1-1> Preparation of6-chloro-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the method shown in reaction formula 2 below.

Step 1: 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) was dissolvedin DMF, followed by lowering the temperature to −10° C.N-iodosuccinimide (1.1 e.q.) was added to the mixture, followed byraising the temperature to room temperature. The mixture was stirred for1 hour. Upon completion of the reaction, iced water was added thereto toinduce precipitation. The formed precipitate was filtered and as aresult a white target compound was obtained (yield: 100%).

Step 2: 4,6-Dichloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) wasdissolved in DMF (0.5 M), followed by lowering the temperature to −78°C. NaH (1.5 e.q.) was added to the mixture above, followed by stirringfor 5 minutes. Upon completion of the reaction, SEM-Cl (1.2 e.q.) wasadded thereto at −78° C. Then, the temperature of the reaction mixturewas raised to room temperature, followed by stirring for 1 hour. Icedwater was added to the reaction mixture above, followed by extractingorganic materials with EtOAc (×3). The collected organic layer waswashed with brine and the remaining water was dried over MgSO₄. Themixture was purified by MPCL (EtOAc:Hex) and as a result a white solidtarget compound was obtained (yield: 100%).

Step 3:4,6-Dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(1.0 e.q.) was dissolved in EtOH, to which methylamine (5.0 e.g., 35 wt% in ethanol) was added at room temperature, followed by stirring at100° C. for 14 hours. Upon completion of the reaction, water was addedthereto to induce precipitation. The formed precipitate was filtered andas a result a target compound was obtained (yield: 86%).

Step 4:6-Chloro-3-iodo-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine(1.0 e.q.) was dissolved in DMF (0.2 M), to which Pd(PPh₃)₄ (0.15 e.q.)and Zn(CN)₂ (2.0 e.q.) were added stepwise under nitrogen atmosphere,followed by raising the temperature to 80° C. After reacting for 14hours, the reaction mixture was cooled to room temperature and dilutedwith EtOAc. The organic layer was washed with sat. NaHCO₃ and brinestepwise and the remaining water was dried over MgSO₄. The mixture waspurified by MPCL (EtOAc:Hex) and as a result a yellow solid targetcompound(6-chloro-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile)was obtained (yield: 57%).

<Preparative Example 1-2> Preparation of6-chloro-4-(ethylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-(ethylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the similar manner to the method described in<Preparative Example 1-1> (yield: 56%).

<Preparative Example 1-3> Preparation of6-chloro-4-(propylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-(propylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the similar manner to the method described in<Preparative Example 1-1> (yield: 67%).

<Preparative Example 1-4> Preparation of6-chloro-4-(2-methoxyethylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-(2-methoxyethylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the similar manner to the method described in<Preparative Example 1-1> (yield: 67%).

<Preparative Example 1-5> Preparation of6-chloro-4-((2-methoxyethyl)(methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-((2-methoxyethyl)(methyl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the similar manner to the method described in<Preparative Example 1-1> (yield: 67%).

<Preparative Example 2-1> Preparation of6-chloro-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the method shown in reaction formula 3 below.

Step 1: 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) was dissolvedin DMF, followed by lowering the temperature to −10° C.N-iodosuccinimide (1.1 e.q.) was added to the mixture, followed byraising the temperature to room temperature. The mixture was stirred for1 hour. Upon completion of the reaction, iced water was added thereto toinduce precipitation. The formed precipitate was filtered and as aresult a white target compound was obtained (yield: 100%).

Step 2: 4,6-Dichloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) wasdissolved in DMF (0.5 M), followed by lowering the temperature to −78°C. NaH (1.5 e.q.) was added to the mixture above, followed by stirringfor 5 minutes. Upon completion of the reaction, SEM-Cl (1.2 e.q.) wasadded thereto at −78° C. Then, the temperature of the reaction mixturewas raised to room temperature, followed by stirring for 1 hour. Icedwater was added to the reaction mixture above, followed by extractingorganic materials with EtOAc (×3). The collected organic layer waswashed with brine and the remaining water was dried over MgSO₄. Themixture was purified by MPCL (EtOAc:Hex) and as a result a white solidtarget compound was obtained (yield: 100%).

Step 3: 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) was dissolvedin methanol (0.1 M), to which Na fragments were added at roomtemperature. The temperature of the mixture was raised to 90° C., andthen refluxed for 14 hours. Upon completion of the reaction, thetemperature of the reaction mixture was lowered to room temperature andwater was added thereto to induce precipitation. The formed precipitatewas filtered and as a result a white target compound was obtained(yield: 80%).

Step 4:6-Chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(1.0 e.q.) was dissolved in DMF (0.2 M) at room temperature, to whichPd(PPh₃)₄ (0.15 e.q.) and Zn(CN)₂ (2.0 e.q.) were added stepwise undernitrogen atmosphere, followed by raising the temperature to 80° C. Afterreacting for 14 hours, the reaction mixture was cooled to roomtemperature and diluted with EtOAc. The organic layer was washed withsat. NaHCO₃ and brine stepwise and the remaining water was dried overMgSO₄. The mixture was purified by MPCL (EtOAc:Hex) and as a result ayellow solid target compound(6-chloro-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile)was obtained (yield: 57%).

<Preparative Example 2-2> Preparation of6-chloro-4-ethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-ethoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the similar manner to the method described in<Preparative Example 2-1> (yield: 67%).

<Preparative Example 2-3> Preparation of6-chloro-4-(1-methylcyclopropoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile

6-Chloro-4-(1-methylcyclopropoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the similar manner to the method described in<Preparative Example 2-1> (yield: 67%).

<Preparative Example 3-1> Preparation of6-chloro-N-methyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine

6-Chloro-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrilewas prepared by the method shown in reaction formula 4 below.

Step 1: 4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) was dissolvedin DMF, followed by lowering the temperature to −10° C.N-iodosuccinimide (1.1 e.q.) was added to the mixture, followed byraising the temperature to room temperature. The mixture was stirred for1 hour. Upon completion of the reaction, iced water was added thereto toinduce precipitation. The formed precipitate was filtered and as aresult a white target compound was obtained (yield: 100%).

Step 2: 4,6-Dichloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (1.0 e.q.) wasdissolved in DMF (0.5 M), followed by lowering the temperature to −78°C. NaH (1.5 e.q.) was added to the mixture above, followed by stirringfor 5 minutes. Upon completion of the reaction, SEM-Cl (1.2 e.q.) wasadded thereto at −78° C. Then, the temperature of the reaction mixturewas raised to room temperature, followed by stirring for 1 hour. Icedwater was added to the reaction mixture above, followed by extractingorganic materials with EtOAc (×3). The collected organic layer waswashed with brine and the remaining water was dried over MgSO₄. Themixture was purified by MPCL (EtOAc:Hex) and as a result a white solidtarget compound was obtained (yield: 100%).

Step 3:4,6-Dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine(1.0 e.q.) was dissolved in EtOH, to which methyl amine (5.0 e.g., 35 wt% in ethanol) was added at room temperature. The mixture was stirred at100° C. for 14 hours. Upon completion of the reaction, water was addedthereto to induce precipitation. The formed precipitate was filtered andas a result a target compound was obtained (yield: 86%).

Step 4: A two-necked round-bottom flask was filled with nitrogen gas, towhich CuI (5.0 e.q.) and KF (5.0 e.q.) were added. The temperature ofthe mixture was raised to 150° C., followed by stirring under reducedpressure for 2 hours. Upon completion of the reaction, the temperaturewas lowered to room temperature. Trimethyl(trifluoromethyl)silane (5.0e.q.) dissolved in DMF/NMP (1:1) was added thereto using a syringe inthe presence of nitrogen. After reacting for 30 minutes,6-chloro-3-iodo-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine(1.0 e.q.) dissolved in DMF/NMP (1:1) was added thereto using a syringe,followed by reaction at 45° C. for 48 hours. Upon completion of thereaction, water was added to the reactant to induce precipitation, andthe formed precipitate was removed by filtration. Organic materials wereextracted from the collected filtrate with EtOAc (×3). The collectedorganic layer was washed with brine and the remaining water was driedover Na₂SO₄. The mixture was purified by MPCL (EtOAc:Hex) and as aresult a white solid target compound was obtained (yield: 58%).

<Preparative Example 3-2> Preparation of6-chloro-N-ethyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine

6-Chloro-N-ethyl-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-aminewas prepared by the similar manner to the method described in<Preparative Example 3-1> (yield: 67%).

<Preparative Example 3-3> Preparation of6-chloro-N-(2-methoxyethyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-amine

6-Chloro-N-(2-methoxyethyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-aminewas prepared by the similar manner to the method described in<Preparative Example 3-1>.

<Example 1> Preparation 1 of the Compound According to the PresentInvention

The pyrrolo-pyridine derivative compound according to the presentinvention was prepared by the method shown in reaction formula 5 below.

Step 1: The6-chloro-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(1.0 e.q.) prepared in <Preparative Example 1-1>,(4-amino-3-methoxyphenyl) (morpholino)methanone (1.0 e.q.) and K₂CO₃(5.0 e.q.) were dissolved in sec-BuOH (0.1 M), followed byultrasonication for 1 minute to eliminate gas. Pd₂(dba)₃ (0.1 e.q.) andXphos (0.1 e.q.) were added to the reaction mixture at 100° C., followedby reaction for 2 hours. Upon completion of the reaction, the reactionmixture was filtered with celite and then washed with EtOAc and MeOH.The obtained filtrate was concentrated and as a result a yellow solidtarget compound(6-(2-methoxy-4-(morpholine-4-carbonyl)phenylamino)-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile)was obtained.

Step 2: The6-(2-methoxy-4-(morpholine-4-carbonyl)phenylamino)-4-(methylamino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile(1.0 e.q.) prepared in step 1 above was dissolved in CH₂Cl₂ (0.05 M), towhich TFA (100 e.q.) was added at room temperature. After reacting 4hours, the solvent was eliminated. The concentrated reaction mixture wasdissolved in THF (0.03 M) again, to which sat. Na₂CO₃ (0.03 M) was addedat room temperature, followed by reaction for 14 hours. Upon completionof the reaction, the resulting product was diluted in EtOAc, and thenwashed with water and brine stepwise. The organic layer was dried overMgSO₄. The mixture was purified by prep-HPLC and as a result a yellowsolid target compound(6-(2-methoxy-4-(morpholine-4-carbonyl)phenylamino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile)was obtained (yield: 67%).

<Example 2>˜<Example 105> Preparation 2 of the Compound According to thePresent Invention

The pyrrolo-pyridine derivatives of the present invention were preparedby the similar manner to the method described in Example 1 using thecompounds of <Preparative Example 1-1>˜<Preparative Example 1-5>,<Preparative Example 2-1>˜<Preparative Example 2-3> and <PreparativeExample 3-1>˜<Preparative Example 3-3>. Chemical structural formulas ofthe compounds of Examples 1˜105 are shown in Tables 1˜3 below. Compoundnames, H1 NMR data, yields and HPLC results are summarized in Table 4below.

TABLE 1 Example Chemical Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

TABLE 2 Example Chemical Structure 37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

TABLE 3 Example Chemical Structure  73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

—  

TABLE 4 HPLC r.t. Yield (min) Example Name ¹H NMR; MS(ESI) m/z (%)(method) 1 6-((2-methoxy-4-(morpholine-4- ¹H NMR (400 MHz, TFA salt,DMSO-d₆) δ 12.15 67 1.762(B) carbonyl)phenyl)amino)-4- (br s, 1H), 8.49(br s, 1H), 8.31 (br s, 1H), (methylamino)-1H-pyrrolo[2,3- 7.87 (d, J =2.1 Hz, 1H), 7.07 (s, 1H), 6.99 b]pyridine-3-carbonitrile (dd, J = 1.5,8.2 Hz, 1H), 6.14 (s, 1H), 3.89 (s, 3H), 3.62 (br s, 4H), 3.54 (br s,4H), 2.89 (S, 3H); 407 [M + H]⁺ 2 4-(ethylamino)-6-((2-methoxy-4- ¹H NMR(400 MHz, TFA salt, DMSO-d6) δ 82 4.75(morpholine-4-carbonyl)phenyl)amino)- 12.10 (s, 1H), 8.47 (br s, 1H),8.34 (br s, 1H-pyrrolo[2,3-b]pyridine-3- 1H), 7.85 (s, 1H), 7.04 (s,1H), 6.96 (d, J = carbonitrile 8.2 Hz, 1H), 6.24 (s, 1H), 5.51 (br s,1H), 3.89 (s, 3H), 3.67-3.44 (m, 8H), 3.27 (m, 2H), 1.24 (t, J = 7.1 Hz,3H); 421 [M + H]⁺ 3 6-((2-methoxy-4-(4- 534 [M + H]⁺ 48 3.984morpholinopiperidine-1- carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H- pyrrolo[2,3-b]pyridine-3- carbonitrile 46-((2-methoxy-4-(morpholine-4- ¹H NMR (400 MHz, DMSO-d6) δ 12.11 (s,1H), 81 4.768 carbonyl)phenyl)amino)-4-((2- 8.63 (d, J = 8.6 Hz, 1H),8.07 (s, 1H), 7.84 methoxyethyl)amino)-1H- (s, 1H), 7.02 (s, 1H), 6.95(d, J = 8.3 Hz, pyrrolo[2,3-b]pyridine-3- 1H), 6.33 (s, 1H), 5.38 (t, J= 5.4 Hz, 1H), carbonitrile 3.90 (s, 3H), 3.62-3.59 (m, 12H), 3.32 (s,3H); 451 [M + H]⁺ CH₂Cl₂/Hexrecrystallization 5 4-((2- ¹H NMR (400 MHz,DMSO-d6) δ 11.99 (s, 1H), 66 5.071 methoxyethyl)amino)-6-((3,4,5- 8.76(s, 1H), 7.83 (s, 1H), 7.14 (s, 2H), 5.84 trimethoxyphenyl)amino)-1H-(s, 1H), 5.35 (m, 1H), 3.76 (s, 6H), 3.59 (m, pyrrolo[2,3-b]pyridine-3-7H), 3.31 (s, 3H); 398 [M + H]⁺ carbonitrile CH₂Cl₂/Hexrecrystallization6 4-((2- 312 [M + H]⁺ 36 4.271 methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H- pyrrolo[2,3-b]pyridine-3- carbonitrile 74-((2-methoxyethyl)amino)-6- ¹H NMR (400 MHz, TFA salt, DMSO-d6) δ 12.0457 4.071 ((1-methyl-1H-pyrazol-3- (s, 1H), 9.04 (s, 1H), 7.92 (s, 1H),7.83 (s, yl)amino)-1H-pyrrolo[2,3- 1H), 5.96 (br s, 1H), 5.76 (s, 2H),3.82 (s, b]pyridine-3-carbonitrile 3H), 3.59 (br s, 2H), 3.40 (br s,2H), 3.31 (s, 3H); 312 [M + H]⁺ 8 4-(ethylamino)-6-((3,4,5- ¹H NMR (400MHz, DMSO-d6) δ 11.97 (S, 1H), 68 5.148 trimethoxyphenyl)amino)-1H- 8.75(s, 1H), 7.82 (s, 1H), 7.14 (s, 2H), 5.82 pyrrolo[2,3-b]pyridine-3- (s,1H), 5.26 (br t, J = 5.3 Hz, 1H), 3.76 (s, carbonitrile 6H), 3.59 (s,3H), 3.22 (m, 2H), 1.24 (t, J = 7.1 Hz, 3H); 398 [M + H]⁺CH₂Cl₂/Hexrecrystallization 9 6-((2-methoxy-4-(4- ¹H NMR (400 MHz, TFAsalt, DMSO-d6) δ 12.09 50 4.336 morpholinopiperidine-1- (s, 1H), 9.90(s, 1H), 8.55 (d, J = 8.0 Hz, carbonyl)phenyl)amino)-4- 1H), 8.21 (br s,1H), 7.84 (s, 1H), 7.01 (s, (propylamino)-1H-pyrrolo[2,3- 1H), 6.96 (d,J = 8.2 Hz, 1H), 6.27 (s, 1H), b]pyridine-3-carbonitrile 5.42 (br s,1H), 4.02 (br d, J = 11.6 Hz, 2H), 3.89 (s, 3H), 3.60-3.42 (m, 7H), 3.19(br t, J = 6.8 Hz, 2H), 3.13 (m, 2H), 2.96 (m, 2H), 3.09 (m, 2H), 1.67(m, 2H), 1.58 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H); 518 [M + H]⁺ 106-((2-methoxy-4-(morpholine-4- ¹H NMR (400 MHz, TFA salt, DMSO-d6) δ12.11 36 5.134 carbonyl)phenyl)amino)-4- (s, 1H), 8.44 (br s, 1H), 8.37(br s, 1H), (propylamino)-1H-pyrrolo[2,3- 7.85 (s, 1H), 7.04 (s, 1H),6.96 (d, J = 8.2 b]pyridine-3-carbonitrile Hz, 1H), 6.24 (s, 1H), 5.53(br s, 1H), 3.60 (m, 4H), 3.52 (m, 4H), 3.19 (t, J = 7.0 Hz, 2H), 1.65(m, 2H), 0.97 (t, J = 7.3 Hz, 3H): 435 [M + H]⁺ 114-(propylamino)-6-((3,4,5- ¹H NMR (400 MHz, TFA salt, DMSO-d6) δ 11.9935 5.307 trimethoxyphenyl)amino)-1H- (s, 1H), 8.85 (br s, 1H), 7.84 (s,1H), 7.09 pyrrolo[2,3-b]pyridine-3- (s, 2H), 5.83 (s, 1H), 5.45 (br s,1H), 3.77 carbonitrile (s, 6H), 3.60 (s, 3H), 3.16 (br t, J = 6.5 Hz,2H), 1.66 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H): 382 [M + H]⁺ 126-((1-methyl-1H-pyrazol-4- ¹H NMR (400 MHz, TFA salt, DMSO-d6) δ 11.9251 4.697 yl)amino)-4-(propylamino)-1H- (s, 1H), 8.90 (br s, 1H), 7.92(s, 1H), 7.80 pyrrolo[2,3-b]pyridine-3- (s, 1H), 7.48 (s, 1H), 5.74 (s,1H), 3.81 (s, carbonitrile 3H), 3.18 (t, J = 7.0 Hz, 2H), 1.66 (m, 2H),0.95 (t, J = 7.3 Hz, 3H): 296 [M + H]⁺ 13 6-((1-methyl-1H-pyrazol-3- ¹HNMR (400 MHz, TFA salt, DMSO-d6) δ 12.76 52 4.973yl)amino)-4-(propylamino)-1H- (br s, 1H), 10.35 (s, 1H), 7.95 (s, 1H),7.69 pyrrolo[2,3-b]pyridine-3- (d, J = 1.8 Hz, 1H), 6.35 (br s, 1H),6.14 carbonitrile (d, J = 1.8 Hz, 1H), 6.13 (s, 1H), 3.82 (s, 3H), 3.24(br s, 2H), 1.67 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H): 296 [M + H]⁺ 144-(ethylamino)-6-((1-methyl-1H- ¹H NMR (400 MHz, TFA salt, DMSO-d6) δ11.85 34 4.696 pyrazol-4-yl)amino)-1H- (s, 1H), 8.89 (s, 1H), 7.75 (s,1H), 7.47 (s, pyrrolo[2,3-b]pyridine-3- 1H), 6.50 (s, 1H), 6.16 (s, 1H),5.18 (t, J = carbonitrile 5.2 Hz, 1H), 3.71 (s, 3H), 3.20 (m, 2H), 1.24(t, J = 7.1 Hz, 3H): 282 [M + H]⁺ 15 4-(ethylamino)-6-((1-methyl-1H- ¹HNMR (400 MHz, TFA salt, DMSO-d6) δ 11.85 46 4.415pyrazol-3-yl)amino)-1H- (s, 1H), 8.54 (s, 1H), 7.90 (s, 1H), 7.72 (s,pyrrolo[2,3-b]pyridine-3- 1H), 7.42 (s, 1H), 5.67 (s, 1H), 5.15 (t, J =carbonitrile 5.3 Hz, 1H), 3.77 (s, 3H), 3.19 (m, 2H), 1.23 (t, J = 7.1Hz, 3H): 282 [M + H]⁺ 16 6-((2-methoxy-4-(4- ¹H NMR (400 MHz, TFA salt,DMSO-d6) δ 12.15 50 4.128 morpholinopiperidine-1- (br s, 1H), 9.98 (brs, 1H), 8.39 (br s, 2H), carbonyl)phenyl)amino)-4- 7.85 (d, J = 2.6 Hz,1H), 7.02 (s, 1H), 6.96 (methylamino)-1H-pyrrolo[2,3- (dd, J = 1.6, 8.2Hz, 1H), 6.15 (s, 1H), 4.01 b]pyridine-3-carbonitrile (d, J = 11.6 Hz,4H), 3.88 (s, 3H), 3.66 (t, J = 11.9 Hz, 3H), 3.49-3.41 (m, 4H), 3.12(br s, 2H), 2.09-2.07 (m, 2H), 1.62-1.54 (m, 2H); 490 [M + H]⁺ 176-((5-fluoro-2-methoxy-4-(4- ¹H NMR (400 MHz, TFA salt, DMSO-d6) δ 12.1650 4.273 morpholinopiperidine-1- (br s, 1H), 9.95 (br s, 1H), 8.64 (d, J= 12.9 carbonyl)phenyl)amino)-4- Hz, 1H), 8.35 (br s, 1H), 7.86 (d, J =2.9 (methylamino)-1H-pyrrolo[2,3- Hz, 1H), 6.90 (d, J = 6.4 Hz, 1H),6.30 (s, b]pyridine-3-carbonitrile 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.01(d, J = 12.0 Hz, 2H), 3.87 (s, 3H), 3.68-3.62 (m, 3H), 3.44 (br s, 3H),3.10 (br s, 3H), 2.85 (s, 3H), 2.78-2.72 (m, 1H), 2.16-2.05 (m, 2H),1.56-1.54 (m, 2H); 508 [M + H]⁺ 18 4-(ethylamino)-6-((2-methoxy-4-(4-504 [M + H]⁺ 69 4.112 morpholinopiperidine-1- carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3- carbonitrile 19 6-((5-fluoro-2-methoxy-4- ¹HNMR (400 MHz, TFA salt, DMSO-d₆) δ 12.18 82 1.839(B) (morpholine-4- (brs, 1H), 8.58 (d, J = 12.8 Hz, 1H), 8.40 carbonyl)phenyl)amino)-4- (br s,1H), 7.86 (d, J = 2.9 Hz, 1H), 6.94 (d, (methylamino)-1H-pyrrolo[2,3- J= 6.4 Hz, 1H), 6.28 (s, 1H), 3.88 (s, 3H), b]pyridine-3-carbonitrile3.63 (br s, 4H), 3.55 (br s, 2H), 3.31 (br s, 2H), 2.86 (s, 3H); 425[M + H]⁺ 20 6-((2-methoxy-4-(morpholine-4- ¹H NMR (400 MHz, TFA salt,DMSO-d6)δ 12.4 3 5.013 carbonyl)phenyl)amino)-4-((2- (s, 1H), 8.59 (d, J= 8.28 Hz, 1H), 8.29 (s, methoxyethyl)(methyl)amino)-1H- 1H), 7.96 (s,1H), 7.03 (s, 1H), 6.96 (d, J = pyrrolo[2,3-b]pyridine-3- 8.28 Hz, 1H),6.57 (s, 1H), 3.90 (s, 3H), carbonitrile 3.61-3.53 (m, 12H), 3.21 (s,3H), 2.98 (s, 3H); 465 [M + H]⁺ 21 6-((5-fluoro-2-methoxy-4- ¹H NMR (400MHz, TFA salt, DMSO-d₆)δ 12.32 2 5.655 (morpholine-4- (s, 1H), 8.68 (d,J = 12.92 Hz, 1H), 8.46 (s, carbonyl)phenyl)amino)-4-((2- 1H), 8.00 (s.1H), 6.94 (d, J = 6.4 Hz, 1H), methoxyethyl)(methyl)amino)-1H- 6.66 (s,1H), 3.89 (s, 3H), 3.63-3.57 (m, pyrrolo[2,3-b]pyridine-3- 10H), 3.32(s, 2H), 3.20 (s, 3H), 2.98 (s, carbonitrile 3H); 483 [M + H]⁺ 22(R)-6-((2-methoxy-4-(2- ¹H NMR (400 MHz, TFA salt, DMSO-d₆)δ 12.07 174.724 methylmorpholine-4- (s, 1H), 8.55 (br, 1H), 8.13 (s, 1H), 7.83 (d,carbonyl)phenyl)amino)-4- J = 2.8 Hz, 1H), 7.02 (s, 1H), 6.96-6.94 (m,(methylamino)-1H-pyrrolo[2,3-b] 1H), 6.20 (s, 1H), 3.89 (s, 3H),3.85-3.78 (m, pyridine-3-carbonitrile 2H), 2.86 (s, 3H), 2.67-2.66 (m,1H), 2.33-2.32 (m, 4H), 1.08 (d, J = 4.4 Hz, 3H); 421 [M + H]⁺ 23(S)-6-((2-methoxy-4-(2- ¹H NMR (400 MHz, TFA salt, DMSO-d₆)δ 12.07 195.033 methylmorpholine-4-carbonyl) (s, 1H), 8.48 (br, 1H), 8.28 (s, 1H),7.83 (d, phenyl)amino)-4-(methylamino)-1H- J = 2.6 Hz, 1H), 7.03 (s,1H), 6.97-6.94 (m, pyrrolo[2,3-b]pyridine-3- 1H), 6.18 (s, 1H), 3.89 (s,3H), 3.85-3.78 (m, carbonitrile 2H), 2.87 (s, 3H), 2.73-2.32 (m, 4H),2.34-2.30 (m, 3H); 421 [M + H]⁺ 24 6-((4-((2R,6S)-2,6- ¹H NMR (400 MHz,TFA salt, DMSO-d₆)δ 12.07 18 5.234 dimethylmorpholine-4-carbonyl)-2- (s,1H), 8.54 (br, 1H), 8.18 (s, 1H), 7.83 (d, methoxyphenyl)amino)-4- J =2.9 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), (methylamino)-1H-pyrrolo[2,3-6.96-6.93 (m, 1H), 6.19 (s, 1H), 3.89 (s, 3H), b]pyridine-3-carbonitrile3.57-3.52 (m, 2H), 2.86 (s, 3H), 2.70-2.32 (m, 4H), 1.19-0.97 (m, 6H);435 [M + H]⁺ 25 6-((4-(4,4- ¹H NMR (400 MHz, TFA salt, DMSO-d₆)δ 12.0719 5.478 difluoropiperidine-1-carbonyl)-2- (s, 1H), 8.60 (br, 1H), 8.09(s, 1H), 7.82 (d, methoxyphenyl)amino)-4- J = 2.9 Hz, 1H), 7.06 (d, J =1.4 Hz, 1H), (methylamino)-1H-pyrrolo [2,3- 7.00-6.97 (m, 1H), 6.21 (s,1H), 3.90 (s, 3H), b]pyridine-3-carbonitrile 3.66-3.57 (m, 4H), 2.90 (s,3H), 2.08-2.00 (m, 4H); 441 [M + H]⁺ 26 (R)-4-(ethylamino)-6- ¹H NMR(400 MHz, TFA salt, DMSO-d₆)δ 12.12 48 4.986 ((2-methoxy-4-(2- (s, 1H),8.38 (NH, 2H), 7.85 (s, 1H), 7.05 (s, methylmorpholine-4- 1H), 6.98 (d,J = 8.2 Hz, 1H), 6.22 (s, 1H), carbonyl)phenyl)amino)-1H- 5.33-4.52 (m,4H), 3.89 (s, 3H), 3.86-3.77 (m, pyrrolo[2,3-b]pyridine-3- 1H),3.56-3.43 (m, 2H), 3.32-3.23 (m, 2H), 1.27 carbonitrile (t, J = 7.1 Hz,3H), 1.08 (s, 3H); 435 [M + H]⁺ 27 (S)-4-(ethylamino)-6- ¹H NMR (400MHz, TFA salt, DMSO-d₆)δ 12.14 47 4.992 ((2-methoxy-4-(2- (s, 1H), 8.38(NH, 2H), 7.87 (s, 1H), 7.07 (s, methylmorpholine-4- 1H), 6.99 (d, J =8.2 Hz, 1H), 6.22 (s, 1H), carbonyl)phenyl)amino)-1H- 5.33-4.52 (m, 4H),3.90 (s, 3H), 3.86-3.78 (m, pyrrolo[2,3-b]pyridine-3- 1H), 3.56-3.43 (m,2H), 3.32-3.23 (m, 2H), 1.28 carbonitrile (t, J = 7.1 Hz, 3H), 1.10 (s,3H); 435 [M + H]⁺ 28 6-((4-((2R,6S)-2,6- ¹H NMR (400 MHz, TFA salt,DMSO-d₆)δ 12.14 27 5.158 dimethylmorpholine-4-carbonyl)-2- (s, 1H), 8.36(NH, 2H), 7.84 (s, 1H), 7.04 (s, methoxyphenyl)amino)-4- 1H), 6.97 (d, J= 8.2 Hz, 1H), 6.20 (s, 1H), (ethylamino)-1H-pyrrolo[2,3- 5.33-4.52 (m,4H), 3.90 (s, 3H), 3.59-3.48 (m, b]pyridine-3-carbonitrile 2H),3.31-3.22 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.07 (s, 6H); 449 [M + H]⁺29 6-((4-(4,4- ¹H NMR (400 MHz, TFA salt, DMSO-d₆)δ 12.18 34 5.356difluoropiperidine-1-carbonyl)-2- (s, 1H), 8.46 (NH, 2H), 7.87 (s, 1H),7.11 (s, methoxyphenyl)amino)-4- 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.21 (s,1H), (ethylamino)-1H-pyrrolo[2,3- 3.90 (s, 3H), 3.70-3.55 (m, 4H),3.32-3.26 (m, b]pyridine-3-carbonitrile 2H), 2.09-2.01 (m, 4H), 1.28 (t,J = 7.1 Hz, 3H); 455 [M + H]⁺ 30 6-((1,3-dimethyl-1H-pyrazol-4- ¹H NMR(400 MHz, TFA salt, Methanol-d₄)δ 37 4.559 yl)amino)-4-(ethylamino)-1H-7.63 (s, 1H), 7.56 (s, 1H), 5.67 (s, 1H), 3.79 pyrrolo[2,3-b]pyridine-3-(s, 3H), 3.36-3.30 (m, 2H), 2.07 (s, 3H), 1.28 carbonitrile (t, J = 7.2Hz, 3H); 296 [M + H]⁺ 31 6-((1,5-dimethyl-1H-pyrazol-4- ¹H NMR (400 MHz,TFA salt, Methanol-d₄)δ 38 4.546 yl)amino)-4-(ethylamino)-1H- 7.56 (s,1H), 7.40 (s, 1H), 5.67 (s, 1H), 3.77 pyrrolo[2,3-b]pyridine-3- (s, 3H),3.36-3.30 (m, 2H), 2.14 (s, 3H), 1.28 carbonitrile (t, J = 7.2 Hz, 3H);296 [M + H]⁺ 32 4-(ethylamino)-6-((1-isopropyl-3- ¹H NMR (400 MHz, TFAsalt, Methanol-d₄)δ 36 4.892 methyl-1H-pyrazol-4- 7.71 (s, 1H), 7.58 (s,1H), 5.64 (s, 1H), yl)amino)-1H-pyrrolo[2,3- 4.43-4.36 (m, 1H),3.35-3.29 (m, 2H), 2.07 b]pyridine-3-carbonitrile (s, 3H), 1.44 (d, J =6.7 Hz, 6H), 1.28 (t, J = 7.2 Hz, 3H); 324 [M + H]⁺ 334-(ethylamino)-6-((1-isopropyl-5- ¹H NMR (400 MHz, TFA salt,Methanol-d₄)δ 33 4.862 methyl-1H-pyrazol-4- 7.56 (s, 1H), 7.45 (s, 1H),5.64 (s, 1H), yl)amino)-1H-pyrrolo[2,3- 4.55-4.48 (m, 1H) , 3.34-3.29(m, 2H), 2.15 b]pyridine-3-carbonitrile (s, 3H), 1.41 (d, J = 6.6 Hz,6H), 1.27 (t, J = 7.2 Hz, 3H); 324 [M + H]⁺ 346-((1,5-dimethyl-1H-pyrazol-4- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ5 4.302 yl)amino)-4-(methylamino)-1H- 7.64 (s, 1H), 7.49 (s, 1H), 5.73(s, 1H), 3.85 pyrrolo[2,3-b]pyridine-3- (s, 3H), 3.03 (s, 3H), 2.23 (s,3H); 282 carbonitrile [M + H]⁺ 35 6-((1,3-dimethyl-1H-pyrazol-4- ¹H NMR(400 MHz, TFA salt, Methanol-d₄)δ 15 4.242 yl)amino)-4-(methylamino)-1H-7.72 (s, 1H), 7.65 (s, 1H), 5.72 (s, 1H), 3.87 pyrrolo[2,3-b]pyridine-3-(s, 3H), 3.03 (s, 3H), 2.14 (s, 3H); 282 carbonitrile [M + H]⁺ 366-((1-isopropyl-3-methyl-1H- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 124.612 pyrazol-4-yl)amino)-4- 7.79 (s, 1H), 7.66 (s, 1H), 5.70 (s, 1H),(methylamino)-1H-pyrrolo[2,3- 4.51-4.44 (m, 1H), 3.02 (s, 3H), 2.16 (s,3H), b]pyridine-3-carbonitrile 1.52 (d, J = 6.7 Hz, 6 H); 310 [M + H]⁺37 6-((1-isopropyl-5-methyl-1H- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ8 4.644 pyrazol-4-yl)amino)-4- 7.65 (s, 1H), 7.54 (s, 1H), 5.70 (s, 1H),(methylamino)-1H-pyrrolo[2,3- 4.62-4.59 (m, 1H), 3.02 (s, 3H), 2.24 (s,3H), b]pyridine-3-carbonitrile 1.50 (d, J = 6.7 Hz, 6 H); 310 [M + H]⁺38 6-((1-(2-cyanopropan-2- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 224.671 yl)-3-methyl-1H-pyrazol-4- 8.08 (s, 1H), 7.69 (s, 1H), 5.75 (s,1H), 3.05 yl)amino)-4-(methylamino)-1H- (s, 3H), 2.22 (s, 3H), 2.04 (s,6H); 335 pyrrolo[2,3-b]pyridine-3- [M + H]⁺ carbonitrile 396-((3-methoxy-5-(morpholine-4- ¹H NMR (400 MHz, TFA salt,Methanol-d₄)δ7.90 13 4.562 carbonyl)pyridin-2-yl)amino)-4- (s, 1H), 7.75(s, 1H), 7.47 (s, 1H), 6.44 (s, (methylamino)-1H-pyrrolo[2,3- 1H), 3.97(s, 3H), 3.76-3.41 (m, 8H), 2.99 b]pyridine-3-carbonitrile (s, 3H); 408[M + H]⁺ 40 4-(ethylamino)-6-((3-methoxy-5- ¹H NMR (400 MHz, TFA salt,Methanol-d₄)δ 20 4.810 (morpholine-4-carbonyl)pyridin- 7.90 (s, 1H),7.74 (s, 1H), 7.47 (s, 1H), 6.48 2-yl)amino)-1H-pyrrolo[2,3- (s, 1H),3.97 (s, 3H), 3.71-3.47 (m, 8H), b]pyridine-3-carbonitrile 3.40-3.35 (m,2H), 1.29 (t, J = 7.2 Hz, 3H); 422 [M + H]⁺ 416-((5-chloro-1-((3S,4S)-3- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 124.177 fluoro-1-(oxetan-3-yl)piperidin-4- 7.83 (s, 1H), 7.70 (s, 1H),5.71 (s, 1H), yl)-1H-pyrazol-4-yl)amino) 5.23-5.08 (m, 1H), 4.88-4.82(m, 2H), (methylamino)-1H-pyrrolo[2,3-b] 4.79-4.74 (m, 2H), 4.22-4.19(m, 1H), pyridine-3-carbonitrile 3.71-3.64 (m, 1H), 3.35-3.32 (m, 2H),3.01 (s, 3H), 2.94-2.80 (m, 2H), 2.49-2.32(m, 2H); 445 [M + H]⁺ 426-((5-chloro-1-((3S,4S)-3- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 294.406 fluoro-1-(oxetan-3-yl)piperidin-4- 7.69 (s, 1H), 7.56 (s, 1H),5.59 (s, 1H), yl)-1H-pyrazol-4- 5.10-4.95 (m, 1H), 4.74-4.61 (m, 4H),yl)amino)(ethylamino)-1H- 4.12-4.05 (m, 1H), 3.59-3.52 (m, 1H),pyrrolo[2,3-b]pyridine-3- 3.29-3.21 (m, 3H), 2.85-2.79 (m, 1H),carbonitrile 2.74-2.69 (m, 1H), 2.39-2.29 (m, 1H), 2.24-2.19 (m, 1H),1.21 (t, J = 7.2 Hz, 3H); 459 [M + H]⁺ 43 (R)-4-(ethylamino)-6- ¹H NMR(400 MHz, TFA salt, Methanol-d₄)δ 34 4.938((3-methoxy-5-(2-methylmorpholine- 7.90 (s, 1H), 7.75 (s, 1H), 7.47 (s,1H), 6.50 4-carbonyl)pyridin- (s, 1H), 4.51-4.20 (m, 1H), 3.98 (s, 3H),2-yl)amino)-1H-pyrrolo[2,3- 3.93-3.70 (m, 1H), 3.68-3.44 (m, 3H),b]pyridine-3-carbonitrile 3.41-3.36 (m, 2H), 3.07-2.81 (m, 1H),2.78-2.51 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.07 (s, 3H); 436 [M + H]⁺44 (R)-6-((3-methoxy-5-(2- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 264.727 methylmorpholine-4-carbonyl) 7.87 (s, 1H), 7.71 (s, 1H), 7.44 (s,1H), 6.39 pyridin-2-yl)amino)-4- (s, 1H), 4.47-4.16 (m, 1H), 3.94 (s,3H), (methylamino)-1H-pyrrolo[2,3- 3.88-3.67 (m, 1H), 3.65-3.37 (m, 3H),b]pyridine-3-carbonitrile 3.32-3.08 (m, 1H), 2.96 (s, 3H), 2.83-2.48 (m,1H), 1.05 (s, 3H); 422 [M + H]⁺ 45 3-methoxy-4-((4-morpholino-3- 1H NMR(400 MHz, TFA salt, Methanol-d₄) δ 35 4.128(trifluoromethyl)-1H-pyrrolo[2,3- 8.51 (d, J = 8.24 Hz, 1H), 7.55 (s,1H), 7.18 b]pyridin-6-yl)amino)phenyl)(4- (d, J = 1.68 Hz, 1H), 7.15(dd, J = 8.24, methylpiperazin-1-yl)methanone 1.76 Hz, 1H), 6.57 (s,1H), 4.49 (br s, 2H), 4.00 (s, 3H), 3.90 (t, J = 4.32 Hz, 4H), 3.57 (brs, 2H), 3.44 (br s, 2H), 3.22 (br s, 2H), 3.18 (t, J = 4.32, 4H), 2.99(s, 3H); 519 [M + H]⁺ 46 (3-methoxy-4-((4-morpholino-3- 602 [M + H]⁺ 414.795 (trifluoromethyl)-1H-pyrrolo[2,3- b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin- 1-yl)piperidin-1-yl)methanone 474-methoxy-6-((2-methoxy-4-(4- ¹H NMR (400 MHz, TFA salt, DMSO-d₆) δ12.26 33 2.219(B) morpholinopiperidine-1- (br s, 1H), 8.64 (d, J = 8.3Hz, 1H), 8.40 (s, carbonyl)phenyl)amino)-1H- 1H), 7.91 (d, J = 2.9 Hz,1H), 7.02 (d, J = pyrrolo[2,3-b]pyridine-3- 1.6 Hz, 1H), 6.97 (dd, J =1.6, 8.3 Hz, 1H), carbonitrile 6.79 (s, 1H), 4.02 (d, J = 11.6 Hz, 2H),3.93 (s, 3H), 3.91 (s, 3H), 3.43 (d, J = 12.1 Hz, 4H), 3.15-3.11 (m,2H), 2.09 (d, J = 9.0 Hz, 2H), 1.62-1.53 (m, 2H); 491 [M + H]⁺ 484-methoxy-6-((2-methoxy-4- ¹H NMR (400 MHz, TFA salt, DMSO-d₆) δ 12.2817 2.442(B) (morpholine-4- (br s, 1H), 8.63 (d, J = 8.3 Hz, 1H), 8.38(s, carbonyl)phenyl)amino)-1H- 1H), 7.90 (d, J = 2.9 Hz, 1H), 7.04 (d, J= pyrrolo[2,3-b]pyridine-3- 1.8 Hz, 1H), 6.97 (dd, J = 1.8, 8.3 Hz, 1H),carbonitrile 6.79 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.60 (br s, 4H),3.52 (br s, 4H); 408 [M + H]⁺ 49 4-ethoxy-6-((2-methoxy-4-(4- ¹H NMR(400 MHz, TFA salt, DMSO-d₆) δ 12.24 51 2.282(B) morpholinopiperidine-1-(br s, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.39 (s,carbonyl)phenyl)amino)-1H- 1H), 7.91 (d, J = 2.9 Hz, 1H), 7.03 (d, J =pyrrolo[2,3-b]pyridine-3- 1.8 Hz, 1H), 6.98 (dd, J = 1.7, 8.3 Hz, 1H),carbonitrile 6.78 (s, 1H), 4.21 (q, J = 14.0 Hz, 2H), 4.03 (d, J = 11.8Hz, 4H), 3.92 (s, 3H), 3.73-3.64 (m, 4H), 3.51-3.39 (m, 3H), 3.17-3.12(m, 2H), 2.10 (d, J = 8.6 Hz, 2H), 1.64-1.54 (m, 2H), 1.43 (t, J = 7.0Hz, 3H); 505 [M + H]⁺ 50 4-ethoxy-6-((2-methoxy-4- ¹H NMR (400 MHz, TFAsalt, DMSO-d₆) δ 12.26 51 2.525(B) (morpholine-4- (br s, 1H), 8.64 (d, J= 8.3 Hz, 1H), 8.36 (s, carbonyl)phenyl)amino)-1H- 1H), 7.90 (d, J = 2.9Hz, 1H), 6.98 (dd, J = pyrrolo[2,3-b]pyridine-3- 1.8, 8.3 Hz, 1H), 6.77(s, 1H), 4.21 (q, J = carbonitrile 14.0 Hz, 2H), 3.91 (s, 3H), 3.61 (brs, 4H), 3.54 (br s, 4H), 1.43 (t, J = 7.0 Hz, 3H); 422 [M + H]⁺ 51(R)-6-((3-methoxy-5-(2- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 305.055 methylmorpholine- 8.40 (s, 1H), 7.85 (s, 1H), 7.62 (s, 1H), 7.194-carbonyl)pyridin-2- (s, 1H), 3.90 (s, 3H), 3.85-3.74 (m, 1H),yl)amino)-4-(1- 3.55-3.44 (m, 2H), 2.12-2.02 (m, 1H),methylcyclopropoxy)-1H- 1.97-1.88 (m, 1H), 1.62 (s, 3H), 1.55-0.44 (m,pyrrolo[2,3-b]pyridine-3- 1H), 1.17 (s, 3H), 1.10-0.98 (m, 5H); 463carbonitrile [M + H]⁺ 52 6-((3-methoxy-5-(morpholine-4- ¹H NMR (400 MHz,TFA salt, Methanol-d₄)δ 5 5.202 carbonyl)pyridin- 8.01 (s, 1H), 7.95 (s,1H), 7.77 (s, 1H), 7.48 2-yl) amino)-4-(1- (s, 1H), 4.18 (s, 3H),3.88-3.60 (m, 8H), 1.73 methylcyclopropoxy)-1H-pyrrolo (s, 3H),1.23-1.11 (m, 2H), 1.02-0.87 (m, 2 H); [2,3-b]pyridine-3-carbonitrile449 [M + H]⁺ 53 N⁴-ethyl-3-(trifluoromethyl)- ¹H NMR (400 MHz, TFA salt,DMSO-d6) δ 11.76 25 5.552 N⁶-(3,4,5-trimethoxyphenyl)- (s, 1H), 8.99 (brs, 1H), 7.55 (s, 1H), 7.09 1H-pyrrolo[2,3-b]pyridine-4,6- (br s, 2H),5.85 (s, 1H), 5.01 (br s, 1H), diamine 3.77 (s, 6H), 3.61 (s, 3H), 3.27(m, 2H), 1.24 (t, J = 7.1 Hz, 3H): 411 [M + H]⁺ 54N⁴-ethyl-N⁶-(1-methyl-1H- 325[M + H] + — —pyrazol-3-yl)-3-(trifluoromethyl)- 1H-pyrrolo[2,3-b]pyridine-4,6-diamine 55 N⁴-ethyl-N⁶-(1-methyl-1H- ¹H NMR (400 MHz, TFA salt, DMSO-d6)δ 11.64 41 4.986 pyrazol-4-yl)-3-(trifluoromethyl)- (s, 1H), 8.86 (br s,1H), 7.93 (s, 1H), 7.49 1H-pyrrolo[2,3-b]pyridine-4,6- (s, 2H), 5.71 (s,1H), 5.21 (br s, 1H), 3.82 diamine (s, 3H), 3.27 (m, 2H), 1.22 (t, J =7.1 Hz, 3H): 325 [M + H]⁺ 56 (4-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFAsalt, DMSO-d₆) δ 11.85 25 5.228 (trifluoromethyl)-1H-pyrrolo[2,3- (s,1H), 8.38 (br s, 1H), 7.55 (s, 1H), 7.06 b]pyridin-6-yl)amino)-3- (s,1H), 6.98 (d, J = 8.2 Hz, 1H), 6.20 (s,methoxyphenyl)(morpholino)methanone 1H), 5.06 (br s, 1H), 3.89 (s, 3H),3.61 (m, 4H), 3.52 (m, 4H), 3.30 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H): 464[M + H]⁺ 57 (4-((4-(ethylamino)-3- ¹H NMR (400 MHz, HCl salt, DMSO)δ11.99 (s, 24 4.595 (trifluoromethyl)-1H-pyrrolo[2,3- 1H), 11.29 (s, 1H),9.01 (br s, 1H), 8.20 b]pyridin-6-yl)amino)-3- (br s, 1H), 7.59 (s, 1H),7.11 (s, 1H), 7.02 methoxyphenyl)(4- (d, J = 8.1 Hz, 1H), 6.12 (s, 1H),5.41 (br morpholinopiperidin-1-yl)methanone s, 1H), 4.59-3.91 (m, 4H),3.89 (s, 3H), 3.87-3.80 (m, 2H), 3.38-3.19 (m, 5H), 3.15-2.79 (m, 4H),2.25-2.12 (m, 2H), 1.76-1.66 (m, 2H), 1.25 (d, J = 7.1 Hz, 3H); 547 [M +H]⁺ 58 (3-methoxy-4-((4-(methylamino)-3- ¹H NMR (400 MHz, TFA salt,Methanol-d₄) δ 45 1.93(B) (trifluoromethyl)-1H-pyrrolo [2,3- 7.52 7.47(m, 2H), 7.24 (d, J = 1.4 Hz, 1H), b]pyridin-6-yl)amino)phenyl) 7.12(dd, J = 8.0, 1.6 Hz, 1H), 5.94 (s, 1H), (morpholino)methanone 3.93 (s,3H), 3.85 3.64 (m, 6H), 3.64 3.45 (m, 2H), 3.05 (s, 3H); 450 [M + H]⁺ 59(3-methoxy-4-((4-(methylamino)-3- ¹H NMR (400 MHz, TFA salt,Methanol-d₄) δ 48 1.710(B) (trifluoromethyl)-1H-pyrrolo[2,3- 7.55 7.46(m, 2H), 7.23 (d, J = 1.4 Hz, 1H), b]pyridin-6-yl)amino)phenyl)(4- 7.13(dd, J = 8.0, 1.5 Hz, 1H), 5.94 (s, 1H),morpholinopiperidin-1-yl)methanone 4.17 4.00 (m, 2H), 3.93 (s, 3H), 3.873.75 (m, 2H), 3.63 3.44 (m, 4H), 3.30 3.15 (m, 4H), 3.04 (s, 3H), 3.022.85 (m, 1H), 2.36 2.13 (m, 2H), 1.85 1.70 (m, 2H); 533 [M + H]⁺ 60(2-fluoro-5-methoxy-4-((4- ¹H NMR (400 MHz, TFA salt, Methanol-d₄) δ 501.71(B) (methylamino)-3-(trifluoromethyl)- 7.70 (t, J = 9.5 Hz, 2H),7.51 (s, 2H), 7.15 1H-pyrrolo[2,3-b]pyridin-6- (d, J = 5.9 Hz, 2H), 6.06(s, 1H), 3.93 (s, yl)amino)phenyl)(4- 3H), 3.70 3.45 (m, 4H), 3.28 3.15(m, 4H), 3.06 methylpiperazin-1-yl)methanone (s, 3H), 2.98 (s, 3H); 481[M + H]⁺ 61 (3-methoxy-4-((4-(methylamino)-3- ¹H NMR (400 MHz, TFA salt,Methanol-d₄) δ 56 1.63(B) (trifluoromethyl)-1H-pyrrolo[2,3- 7.52 7.47(m, 2H), 7.22 (d, J = 1.2 Hz, 1H), b]pyridin-6-yl)amino)phenyl)(4-(4-7.12 (dd, J = 8.0, 1.4 Hz, 1H), 5.94 (s, 1H),methylpiperazin-1-yl)piperidin-1- 4.82 4.65 (m, 1H), 4.05 3.95 (m, 1H),3.92 (s, yl)methanone 3H), 3.50 3.42 (m, 4H), 3.25 3.11 (m, 4H), 3.05(s, 3H), 3.02 2.93 (m, 1H) 2.92 (s, 3H), 2.20 1.95 (m, 2H), 1.75 1.62(m, 2H); 546 [M + H]⁺ 62 N⁶-(2-methoxy-4-(4- ¹H NMR (400 MHz, TFA salt,Methanol-d₄) δ 57 1.740(B) methylpiperazin-1-yl)phenyl)-N⁴- 7.42 (d, J =1.2 Hz, 1H), 7.25 (d, J = 8.6 methyl-3-(trifluoromethyl)- Hz, 1H), 6.81(d, J = 2.4 Hz, 1H), 6.70 (dd, 1H-pyrrolo[2,3-b]pyridine-4,6- J = 8.6,2.5 Hz, 1H), 5.73 (s, 1H), 3.95 (m, diamine 2H), 3.86 (s, 3H), 3.64 (m,2H), 3.54 3.47 (m, 1H), 3.43 3.38 (m, 1H), 3.28 (m, 2H), 3.19 3.05 (m,2H), 3.00 (s, 3H), 2.99 (s, 3H); 435 [M + H]⁺ 63(3-methoxy-4-((4-(methylamino)-3- ¹H NMR (400 MHz, TFA salt,Methanol-d₄) δ 27 1.670(B) (trifluoromethyl)-1H-pyrrolo[2,3- 7.53 (d, J= 8.0 Hz, 1H), 7.51 7.49 (m, 1H), b]pyridin-6-yl)amino)phenyl) 7.28 (d,J = 1.5 Hz, 1H), 7.17 (dd, J = 8.0, (4-methylpiperazin-1-yl)methanone1.6 Hz, 1H), 5.96 (s, 1H), 3.94 (s, 3H), 3.75 3.40 (m, 4H), 3.40 3.11(m, 4H), 3.05 (s, 3H), 2.97 (s, 3H); 463 [M + H]⁺ 64 (3-methoxy-4-((4-¹H NMR (400 MHz, TFA salt, Methanol-d₄) δ 42 2.03(B)((2-methoxyethyl)amino)-3- 7.51 7.47 (m, 2H), 7.23 (d, J = 1.2 Hz, 1H),(trifluoromethyl)-1H-pyrrolo[2,3- 7.11 (dd, J = 8.0, 1.4 Hz, 1H), 5.99(s, 1H), b]pyridine-6yl)amino)phenyl) 3.92 (s, 3H), 3.83 3.76 (m, 4H),3.68 (t, J = (morpholino)methanone 5.0 Hz, 2H), 3.63 3.47 (m, 4H), 3.52(t, J = 5.1 Hz, 2H), 3.42 (s, 3H); 494 [M + H]⁺ 65 (3-methoxy-4-((4-((2-¹H NMR (400 MHz, TFA salt, Methanol-d₄) δ 64 1.81(B)methoxyethyl)amino)-3- 7.55 7.48 (m, 2H), 7.22 (d, J = 1.4 Hz, 1H),(trifluoromethyl)-1H-pyrrolo[2,3- 7.12 (dd, J = 8.0, 1.6 Hz, 1H), 6.00(s, 1H), b]pyridin-6-yl)amino)phenyl)(4- 4.15 4.00 (m, 5H), 3.92 (s,3H), 3.87 3.75 (m, morpholinopiperidin-1-yl)methanone 4H), 3.68 (t, J =5.2 Hz, 2H), 3.60 3.52 (m, 2H), 3.68 (t, J = 5.2 Hz, 2H), 3.42 (s, 3H),3.27 3.15 (m, 4H), 3.02 2.85 (m, 1H), 2.35 2.10 (m, 2H), 1.85 1.70 (m,2H)); 577 [M + H]⁺ 66 (3-methoxy-4-((4-((2- ¹H NMR (400 MHz, TFA salt,Methanol-d₄) δ 57 1.76(B) methoxyethyl)amino)-3- 7.58 (t, J = 7.9 Hz,1H), 7.51 (d, J = 1.1 (trifluoromethyl)-1H-pyrrolo[2,3- Hz, 1H), 7.27(d, J = 1.6 Hz, 1H), 7.16 (dd, b]pyridin-6-yl)amino)phenyl)(4- J = 8.0,1.7 Hz, 1H), 6.01 (s, 1H), 4.38 (m, methylpiperazin-1-yl)-methanone 1H),3.94 (s, 3H), 3.68 (t, J = 5.2 Hz, 2H), 3.60 (m, 4H), 3.52 (t, J = 5.2Hz, 2H), 3.48 (m, 4H), 3.42 (s, 3H), 3.35 (m, 2H), 3.25 (m, 2H), 2.96(s, 3H); 507 [M + H]⁺ 67 (3-methoxy-4-((4-((2- ¹H NMR (400 MHz, TFAsalt, Methanol-d₄) δ 8 4.399 methoxyethyl)amino)-3- 7.54 7.48 (m, 2H),7.22 (d, J = 1.3 Hz, 1H), (trifluoromethyl)-1H-pyrrolo[2,3- 7.11 (dd, J= 8.0, 1.6 Hz, 1H), 6.00 (s, 1H), b]pyridin-6-yl)amino)phenyl)(4- 4.70(br s, 1H), 3.92 (s, 3H), 3.69 (t, J = methylpiperazin-1-yl)piperidin-1-5.2 Hz, 2H), 3.52 (t, J = 5.2 Hz, 2H), 3.43 (s, yl)methanone 3H), 3.413.32 (m, 4H), 3.27 3.12 (m, 4H), 3.11 2.95 (m, 4H), 2.90 (s, 3H), 2.00(m, 2H), 1.63 (m, 2H); 590 [M + H]⁺ 68 N⁶-(2-methoxy-4-(4- ¹H NMR (400MHz, TFA salt, Methanol-d₄) δ 56 4.686 methylpiperazin-1-yl)phenyl)-N⁴-7.44 (d, J = 1.1 Hz, 1H), 7.26 (d, J = 8.6(2-methoxyethyl)-3-(trifluoromethyl)- Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H),6.70 (dd, 1H-pyrrolo[2,3-b]pyridine-4,6- J = 8.6, 2.4 Hz, 1H), 5.77 (s,1H), 4.02 3.87 diamine (m, 2H), 3.86 (s, 3H), 3.67 (t, J = 5.1 Hz, 2H),3.65 3.55 (m, 1H), 3.52 3.48 (m, 1H), 3.46 (t, J = 5.1 Hz, 2H), 3.443.38 (m, 5H), 3.22 3.05 (m, 2H), 2.99 (s, 3H); 479 [M + H]⁺ 69N⁶-(5-chloro-1-((3S,4S)-3- ¹H NMR (400 MHz, TFA salt, Methanol-d₄) δ 824.877 fluoro-1-(oxetan-3-yl)piperidin-4- 7.84 (s, 1H), 7.51 (s, 1H),5.74 (s, 1H), yl)-1H-pyrazol-4-yl)-N⁴-ethyl-3- 5.11-5.27 (m, 1H), 4.88(m, 5H), 4.28 (m, 1H), (trifluoromethyl)-1H-pyrrolo[2,3- 3.76 (m, 1H),3.43 (m, 3H), 3.00 (m, 1H), 2.92 b]pyridine-4,6-diamine (m, 1H), 2.55(m, 1H), 2.39 (m, 1H), 1.34 (t, J = 6.9 Hz, 3H); 502 [M + H]⁺ 70(4-(ethylamino)-3-(trifluoromethyl)- 560 [M + H]⁺ 14 4.5011H-pyrrolo[2,3-b]pyridin-6- yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin- 1-yl)piperidin-1-yl)methanone 714-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFA salt, Methanol-d₄)δ 68 4.991(trifluoromethyl)- 7.67 (d, J = 12.0 Hz, 1H), 7.54 (s, 1H), 7.411H-pyrrolo[2,3-b]pyridin-6- (d, J = 6.5 Hz, 1H), 6.01 (s, 1H), 4.88 (m,yl)amino)-2-fluoro-5methoxy- 2H), 4.45 (br s, 1H), 4.24 (br s, 1H), 3.96N-(1-(oxetanepiperidin- (s, 3H), 3.58 (br s, 2 H), 3.46 (q, J = 7.24-yl)benzamide Hz, 2H), 3.08 (br s, 2H), 2.33 (m, 2H), 2.05 (br s, 2H),1.37 (t, J = 7.2 Hz, 3H); 551 [M + H]⁺ 72 4-((4-(ethylamino)-3- ¹H NMR(400 MHz, TFA salt, DMSO-d₆) δ 11.90 59 4.994(trifluoromethyl)-1H-pyrrolo[2,3- (s, 1H), 9.49 (d, J = 71.8 Hz, 1H),8.75 8.65 b]pyridin-6-yl)amino)-2- (m, 1H), 8.34 (s, 1H), 8.17 7.95 (m,1H), 7.57 fluoro-5-methoxy-N-(1- (br s, 1H), 7.16 (dd, J = 12.6, 6.9 Hz,1H), methylpiperidin-4-yl)benzylamide 6.38 (s, 1H), 4.82 (br s, 1H),3.91 (s, 3H), 3.52 3.42 (m, 2H), 3.32 3.23 (m, 2H), 3.16 3.02 (m, 2H),2.80 2.76 (m, 3H), 2.10 2.00 (m, 2H), 1.82 1.69 (m, 2H), 1.25 (t, J =7.1 Hz, 3H); 509 [M + H]⁺ 73 2-fluoro-5-methoxy-4-((4- ¹H NMR (400 MHz,TFA salt, DMSO-d₆) δ 11.93 50 4.910 ((2-methoxyethyl)amino)-3- (d, J =2.3 Hz, 1H), 9.52 (d, J = 70.3 Hz, (trifluoromethyl)-1H-pyrrolo[2,3-1H), 8.77 8.67 (m, 1H), 8.36 8.29 (m, 1H), 8.09 b]pyridin-6-yl)amino)(1-7.98 (m, 1H), 7.59 (s, 1H), 7.15 (dd, J = methylpiperidin-4-yl)benzamide12.8, 6.9 Hz, 1H), 6.41 (s, 1H), 5.09 (br s, 1H), 4.20 3.94 (m, 2H),3.91 (d, J = 3.3 Hz, 3H), 3.61 (t, J = 5.3 Hz, 2H), 3.40 3.36 (m, 2H),3.32 ( s, 3H), 3.21 3.03 (m, 2H), 2.80 2.75 (m, 3H), 2.08 2.00 (m, 2H),1.81 1.67 (m, 2H); 539 [M + H]⁺ 74 4-((4-(ethylamino-3- ¹H NMR (400 MHz,TFA salt, DMSO-d₆) δ 11.91 49 5.085 (trifluoromethyl)- 11.87 (m, 1H),9.07 (d, J = 42.5 Hz, 1H), 8.77 1H-pyrrolo[2,3-b]pyridin-6- 8.67 (m,1H), 8.34 (s, 1H), 8.22 8.00 (m, 1H), yl)amino)-2-fluoro-N-(1- 7.57 (s,1H), 7.15 7.10 (m, 1H), 6.38 (s, 1H), isopropylpiperidin-4-yl)-5- 4.81(br s, 1H), 4.11 3.98 (m, 1H), 3.91 (s, methoxybenzamide 3H), 3.51 3.45(m, 1H), 3.45 3.36 (m, 2H), 3.32 3.25 (m, 2H), 3.17 3.05 (m, 2H), 2.152.05 (m, 2H), 1.85 1.73 (m, 2H), 1.33 1.17 (m, 9H); 537 [M + H]⁺ 75(R)-(2,4- ¹H NMR (400 MHz, TFA salt, DMSO) δ 11.86 (s, 47 1.762(B)dimethylpiperazin-1-yl)(2-fluoro- 1H), 9.60 (br s, 1H), 8.76 (br s, 1H),8.33 5-methoxy-4-((4-(methylamino)-3- (s, 1H), 7.55 (s, 1H), 6.92 (br s,1H), 6.31 (trifluoromethyl)-1H-pyrrolo[2,3- (s, 1H), 5.12 (br s, 1H),4.96 (br s, 1H), b]pyridin-6-yl)amino)phenyl)methanone 4.18-4.11 (m,1H), 3.90 (s, 3H), 3.22-3.17 (m, 2H), 3.16-2.92 (m, 2H), 2.89 (s, 3H),2.84 (s, 3H), 1.47-1.23 (m, 3H); 495[M + H]⁺ 76(3-methoxy-4-((4-morpholino-3- ¹H NMR (400 MHz, TFA salt, DMSO) δ 8.24(d, 60 6.108 (trifluoromethyl)-1H-pyrrolo[2,3- J = 8.16 Hz, 1H), 7.55(s, 1H), 7.16 (s, 1H), b] pyridin-6- 7.29 (d, J = 6.48 Hz, 1H), 3.97 (s,3H), 3.89 yl)amino)phenyl)(morpholino)methanone (m, 4H), 3.73 (brs, 8H),3.20 (m, 4H); 506[M + H]⁺ 77 N-(5-chloro-1-((3S,4S)-3- ¹H NMR (400 MHz,TFA salt, DMSO) δ 8.02 (s, 44 5.121 fluoro-1-(oxetane-3-yl)piperidin-1H), 7.54 (s, 1H), 6.23 (s, 1H), 5.29-5.12 (m, 4-yl)-1H-pyrazol-4-yl)-4-1H), 4.89-4.86 (m, 2H), 4.86-4.81 (m, 2H),morpholino-3-(trifluoromethyl)- 4.34-4.29 (m, 1H), 3.88-3.86 (m, 4H),1H-pyrrolo[2,3-b]pyridine-6- 3.79-3.72 (m, 1H), 3.48-3.33 (m, 2H), amine3.22-3.20 (m, 4H), 3.09-2.94 (m, 2H), 2.49-2.37 (m, 2H); 544[M + H]⁺ 78N6-(5-chloro-1-((3S,4S)-3- ¹H NMR (400 MHz, TFA salt, DMSO) δ 7.86 (s,48 4.593 fluoro-1-(oxetan-3-yl)piperidin-4- 1H), 7.50 (s, 1H), 5.73 (s,1H), 5.27-5.10 (m, yl)-1H-pyrazol-4-yl)-N4-methyl- 1H), 4.75-4.83 (m,2H), 4.81-4.77 (m, 2H), 3-(trifluoromethyl)-1H-pyrrolo[2,3- 4.22-4.19(m, 2H), 3.71-3.65 (m, 1H), b]pyridine-4,6-diamine 3.39-3.33 (m, 2H),3.04 (s, 3H), 2.95-2.79 (m, 2H) 2.54-2.33 (m, 2H); 488[M + H]⁺ 79N6-(5-chloro-1-((3S,4S)-3- ¹H NMR (400 MHz, TFA salt, DMSO) δ 7.86 (s,48 4.777 fluoro-1-(oxetan-3-yl)piperidin-4- 1H), 7.51 (s, 1H), 5.80 (s,1H), 5.29-5.17 (m, yl)-1H-pyrazol-4-yl)-3- 1H), 4.89-4.86 (m, 2H),4.85-4.81 (m, 2H), methoxyethyl)-3-(trifluoromethyl)- 4.35-4.32 (m, 1H),3.82-3.75 (m, 1H), 1H-pyrrolo [2,3-b]pyridine-4,6- 3.70-3.67 (m, 2H),3.53-3.50 (m, 4H), 3.43 diamine (s, 3H), 3.13-2.97 (m, 2H), 2.55-2.39(m, 2H); 532[M + H]⁺ 80 1-(6-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFAsalt, DMSO) δ 7.51 (s, 88 5.920 (trifluoromethyl)-1H-pyrrolo[2,3- 1H),7.28 (s, 1H), 7.09 (s, 1H), 5.90 (s, 1H), b]pyridin-6-yl)amino)-7- 4.90(s, 2H), 3.96 (t, J = 5.6 Hz, 2H), 3.91 methoxy-3,4-dihydroisoquinolin-(s, 3H), 3.15 (q, J = 7.12 Hz, 2H), 3.01-3.00 2(1H)-yl)-2,2,2- (m, 2H),1.38 (t, J = 7.16 Hz, 3H); trifluoroethan-1-one 502[M + H]⁺ 81N4-ethyl-N6-(7-methoxy-1,2,3,4- ¹H NMR (400 MHz, TFA salt, DMSO) δ 7.50(s, 41 4.632 tetrahydroisoquinolin-6-yl)-3- 1H), 7.37 (s, 1H), 7.03 (s,1H), 5.87 (s, 1H), (trifluoromethyl)-1H-pyrrolo[2,3- 4.42 (s, 2H), 3.89(s, 3H), 3.53 (t, J = 6.32 b]pyridine-4,6-diamine Hz, 2H), 3.39 (q, J =7.14 Hz, 2H), 3.10 (t, J = 6.16 Hz, 2H), 1.34 (t, J = 7.16 Hz, 2H);406[M + H]⁺ 82 (3-methoxy-4-((4-morpholino-3- ¹H NMR (400 MHz, TFA salt,MeOD-d₄)δ 8.50 43 5.080 (trifluoromethyl)-1H-pyrrolo[2,3- (d, J = 8.24Hz, 1H), 7.55 (s, 1H), 7.18 (s, b]pyridin-6-yl)amino)phenyl)(4- 1H),7.14 (d, J = 8.24 Hz, 1H), 6.57 (s, 1H), methylpiperazin-1-yl)methanone4.49 (brs, 2H), 4.00 (s, 3H), 4.00-3.88 (m, 4H), 3.57 (brs, 2H), 3.49(brs, 2H), 3.22 (brs, 2H), 3.19-3.15 (m, 4H), 2.99 (s, 3H); 519[M + H]⁺83 (3-methoxy-4-((4-morpholino-3- ¹H NMR (400 MHz, TFA salt, MeOD-d₄)δ8.30 49 4.795 (trifluoromethyl)-1H-pyrrolo[2,3- (d, J = 8.2 Hz, 1H),7.55 (s, 1H), 7.14 (s, 1H), b]pyridin-6-yl)amino)phenyl)(4-(4- 7.08 (d,J = 8.2 Hz, 1H), 6.52 (s, 1H), 3.97 (s,methylpiperazin-1-yl)piperidin-1- 3H), 3.90-3.88 (m, 4H), 3.45-3.33 (m,7H), yl)methanone 3.21-3.14 (m, 4H), 3.13-3.10 (m, 3H), 2.93 (s, 3H),2.17-1.99 (m, 2H), 1.70-1.61 (m, 2H); 602[M + H]⁺ 84(3-methoxy-4-(3-(trifluoromethyl)- ¹H NMR (400 MHz, TFA salt, DMSO) δ7.71-7.59 36 6.647 4-(3-(trifluoromethyl) (m, 6H), 7.17 (s, 1H), 7.05(d, J = 7.92 Hz, phenylamino)-1H- 1H), 6.17 (s, 1H), 3.90 (s, 3H), 3.72(br, pyrrolo[2,3-b]pyridin-6- 8H); 579[M + H]⁺ylamino)phenyl)(morpholino)methanone 85(3-methoxy-4-(3-(trifluoromethyl)- ¹H NMR (400 MHz, TFA salt, DMSO) δ8.11-8.09 47 5.540 4-(3-(trifluoromethyl) (m, 2H), 7.79-7.76 (m, 2H),7.68-7.57 (m, 2H), phenylamino)-1H-pyrrolo[2,3- 7.15 (s, 1H), 7.06 (d, J= 9.8 Hz, 1H), 6.28 b]pyridin-6-ylamino)phenyl)(4- (s, 1H), 4.10 (br,2H), 3.92 (s, 3H), 3.82 (br, morpholinopiperidin-1-yl)methanone 2H),3.56-3.53 (m, 3H), 3.25 (br, 2H), 3.10 (br, 4H), 2.24 (br, 2H),1.79-1.74 (m, 2H); 662[M + H]⁺ 86 N6-(5-chloro-1-((3S,4S)-3- ¹H NMR (400MHz, TFA salt, DMSO) δ 7.81 (s, 39 5.789fluoro-1-(oxetan-3-yl)piperidin-4- 1H), 7.68-7.60 (m, 5H), 5.93 (s, 1H),5.20-5.02 yl)-1H-pyrazol-4-yl)-3- (m, 1H), 4.89-4.83 (m, 2H), 4.79-4.74(m, 2H), (trifluoromethyl)-N4-(3- 4.20-4.15 (m, 1H), 3.66-3.60 (m, 1H),(trifluoromethyl)phenyl)-1H- 3.33-3.32 (m, 1H), 2.85-2.68 (m, 2H),pyrrolo[2,3-b]pyridine-4,6- 2.45-2.22 (m, 2H); 618[M + H]⁺ diamine 87(3-methoxy-4-((4- ¹H NMR (400 MHz, TFA salt, MeOD) δ 7.66 (d, 64 5.670methoxyethyl)(methyl)amino)-3- J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.23 (s,1H), (trifluoromethyl)-1H-pyrrolo[2,3- 7.14 (d, J = 8.0 Hz, 1H), 6.28(s, 1H), 3.95 b]pyridin-6-yl)amino)phenyl) (s, 3H), 3.88-3.52 (m, 12H),3.28 (s, 3H), (morpholino)methanone 3.12 (s, 3H); 508[M + H]⁺ 88(3-methoxy-4-((4- ¹H NMR (400 MHz, TFA salt, MeOD) δ 7.78 (d, 45 4.848methoxyethyl)(methyl)amino)-3- J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.22 (s,1H), (trifluoromethyl)-1H-pyrrolo[2,3- 7.14 (d, J = 8.1 Hz, 1H), 6.32(s, 1H), b]pyridin-6-yl)amino)phenyl)((4- 4.20-4.02 (m, 2H), 3.96 (s,3H), 3.89-3.70 (m, morpholinopiperidin-1-yl)methanone 2H), 3.65 (s, 4H),3.61-3.50 (m, 2H), 3.25-3.15 (m, 5H), 3.10 (s, 3H), 2.40-2.15 (m, 2H),1.81-1.69 (m, 2 H); 590[M + H]⁺ 89 N6-(5-chloro-1-((3S,4S)-3-fluoro- ¹HNMR (400 MHz, TFA salt, DMSO) δ 7.88 (s, 54 4.9591-(oxetan-3-yl)piperidin-4- 1H), 7.58 (s, 1H), 6.04 (s, 1H), 5.27-5.10(m, yl)-1H-pyrazol-4-yl)methoxyethyl)- 1H), 4.86 (m, 2H), 4.381-4.78 (m,2H), N4-methyl-3-(trifluoromethyl)- 4.26-4.21 (m, 1H), 3.68-3.67 (m,3H), 1H-pyrrolo[2,3-b]pyridine-4,6- 3.65-3.64 (m, 2H), 3.42-3.35 (m,1H), 3.27 diamine (s, 3H), 3.12 (s, 3H), 2.96-2.83 (m, 2H), 2.54-2.33(m, 2H); 546[M + H]⁺ 90 (4-(4-(isopropylamino)-3- ¹H NMR (400 MHz, TFAsalt, MeOD-d₄)δ 7.54- 13 4.845 (trifluoromethyl)-1H-pyrrolo[2,3- 7.52(m, 2H), 7.23 (s, 1H), 7.14 (d, J = 8.04 b]pyridin-6-ylamino)-3- Hz,1H), 5.98 (s, 1H), 4.09-3.98 (m, 3H), 3.93 methoxyphenyl)(4- (s, 3H),3.89-3.84 (m, 3H), 3.55-3.40 (m, 4H), morpholinopiperidin-1-yl)methanone3.33-3.13 (m, 4H), 2.24-2.15 (m, 2H), 1.77-1.74 (m, 2H), 1.35 (d, J =6.28 Hz, 6H); 561[M + H]⁺ 91 (R)-(4-((4-((1-hydroxy-3- ¹H NMR (400 MHz,TFA salt, MeOD) δ 7.41 (s, 37 4.724 methylbutan-2-yl)amino)-3- 1H), 7.37(d, J = 8.0 Hz, 1H), 7.11 (s, 1H), (trifluoromethyl)-1H-pyrrolo[2,3-7.02 (d, J = 8.0 Hz, 1H), 5.93 (s, 1H), b]amino)-3-methoxyphenyl)(4-4.05-3.91 (m, 2H), 3.81 (s, 3H), 3.75-3.60 (m,morpholinopiperidin-1-yl)methanone 4H), 3.50-3.46 (m, 4H), 3.23-2.70 (m,5H), 2.24-1.96 (m, 3 H), 1.73-1.59 (m, 2H), 0.97-0.90 (m, 7H); 605[M +H]⁺ 92 (R)-(4-((4-((1-hydroxy-3- ¹H NMR (400 MHz, TFA salt, MeOD) δ 7.42(s, 54 5.316 methylbutan-2-yl)amino)-3- 1H), 7.39 (d, J = 8.0 Hz, 1H),7.14 (s, 1H), (trifluoromethyl)-1H-pyrrolo[2,3- 7.04 (d, J = 8.0 Hz,1H), 5.95 (s, 1H), 3.83 b]amino)-3- (s, 3H), 3.70-3.40 (m, 9H),2.06-1.99 (m, 1H), methoxyphenyl)(morpholino)methanone 0.96 (t, J = 7.2Hz, 6H); 522[M + H]⁺ 93 (S)-(4-((4-(2-butylamino)-3- ¹H NMR (400 MHz,TFA salt, MeOD) δ 7.41 (s, 45 5.034 (trifluoromethyl)-1H-pyrrolo[2,3-1H), 7.40 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), b]pyridin-6-yl)amino)-3-6.75 (d, J = 8.0 Hz, 1H), 5.86 (s, 1H), methoxyphenyl)(4- 4.08-3.96 (m,2H), 3.82 (s, 3H), 3.79-3.51 (m, morpholinopiperidin-1-yl)-methanone3H), 3.49-3.35 (m, 3H), 3.29-3.04 (m, 4H), 2.25-2.04 (m, 2H), 1.84-1.63(m, 4H), 1.27-1.18 (m, 4H), 0.96-0.84 (m, 4H); 575[M + H]⁺ 94(4-((4-(cyclopropylamino)-3- ¹H NMR (400 MHz, TFA salt, MeOD-d₄) δ 7.6233 4.712 (trifluoromethyl)-1-((2- (d, J = 8.18 Hz, 1H), 7.50 (s, 1H),7.24 (s, (trimethylsilyl)ethoxy)methyl)- 1H), 7.15 (d, J = 7.72 Hz, 1H),6.42 (s, 1H), 1H-pyrrolo[2,3-b]pyridin-6-yl)3- 4.10-3.99 (m, 2H),3.98-3.94 (m, 1H), 3.94 methoxyphenyl)(4- (s, 3H), 3.93-3.79 (m, 2H),3.72-3.49 (m, 3H), morpholinopiperidine-1-yl)methanone 3.34-3.13 (m,5H), 2.70-2.65 (m, 1H), 2.40-2.14 (m, 2H), 1.85-1.60 (m, 2H), 1.00-0.94(m, 2H), 0.76-0.68 (m, 2H); 559[M + H]⁺ 95 (4-((4-(cyclopropylamino)-3-¹H NMR (400 MHz, TFA salt, MeOD) δ 7.61 (J = 16 5.431(trifluoromethyl)-1H-pyrrolo[2,3- 8.0 Hz, 1H), 7.49 (s, 1H), 7.23 (s,1H), 7.14 b]pyridin-6-yl)amino)-3- (J = 8.0 Hz, 1H), 6.41 (s, 1H), 3.94(s, 1H), methoxyphenyl)(morpholino)methanone 3.86-3.45 (m, 8H),2.72-2.66 (m, 1H), 0.98-0.90 (m, 2H), 0.85-0.50 (m, 2 H); 476[M + H]⁺ 965-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFA salt, DMSO) δ 11.88 (br 422.05(B) (trifluoromethyl)-1H-pyrrolo[2,3- s, 1H), 8.67 (br s, 1H), 8.33(br s, 1H), b]pyridin-6-yl)amino)-6- 7.56 (br s, 1H), 7.20 (s, 1H), 6.27(s, 1H), methoxy-2-methylisoindolin-1-one 4.93 (br s, 1H), 4.35 (s, 2H),3.94 (s, 3H), 3.32-3.26 (m, 2H), 3.05 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H);420[M + H]⁺ 97 7-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFA salt,MeOD-d₄)δ 7.46 57 5.77 (trifluoromethyl)-1H-pyrrolo[2,3- (d, J = 1.16Hz, 1H), 7.00 (s, 1H), 6.90 (s, b]pyridin-6-yl)amino)-6- 1H), 5.81 (s,1H), 3.98 (s, 3H), 3.40 (s, 3H), methoxy-2,2,4-trimethyl-2H- 3.89-3.35(m, 2H), 1.47 (s, 6H), 1.34-1.30 (m, benzo[1,4]oxazin-3(4H)-1-one 3H);464[M + H]⁺ 98 6-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFA salt,MeOD-d₄)δ 7.75 8 5.19 (trifluoromethyl)-1H-pyrrolo[2,3- (s, 1H), 7.48(d, J = 1.32 Hz, 1H), 7.40 b]pyridin-6-yl)amino)-5-methoxy- (s, 1H),5.92 (s, 1H), 4.54 (s, 2H), 3.98 (s, 2-methylisoindolin-1-one 3H),3.44-3.39 (m, 2H), 3.20 (s, 3H), 1.35-1.31 (m, 3H); 420[M + H]⁺ 994-(ethylamino)-6-((6-methoxy-2- ¹H NMR (400 MHz, TFA salt, MeOD-d₄)δ7.84 3 4.76 methyl-3-oxoisoindol-5- (s, 1H), 7.68 (s, 1H), 7.38 (s, 1H),5.92 (s, yl)amino)-1H-pyrrolo[2,3- 1H), 4.53 (s, 2H), 3.98 (s, 3H),3.42-3.39 (m, b]pyridine-3-carbonitrile 2H), 3.20 (s, 3H), 1.37-1.33 (m,3H); 377[M + H]⁺ 100 6-((2(2-cyanopropan-2- ¹H NMR (400 MHz,Methanol-d₄)δ7.45 (s, 60 5.25 yl)-4-methylthiazol-5- 1H), 5.86 (s, 1H),3.24-3.20 (m, 2H), 2.29 yl)amino)-4-(ethylamino)-1H- (s, 3H), 1.73 (s,6H), 1.25 (t, J = 7.2 Hz, pyrrolo[2,3-b]pyridine-3- 3H); 366[M + H]⁺carbonitrile 101 (6-chloro-5-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFAsalt, DMSO) δ 11.90 (br 8 2.07(B) (trifluoromethyl)-1H-pyrrolo[2,3- s,1H), 8.61 (s, 1H), 8.30 (br s, 1H), 7.65 b]pyridin-6-yl)amino)-2- (s,1H), 7.57 (br s, 1H), 6.35 (s, 1H), 4.88 methylisoindolin-1-one (br s,1H), 4.39 (s, 2H), 3.30-3.28 (m, 2H), 3.04 (s, 3H), 1.24 (t, J = 7.1 Hz,3H); 424 [M + H]⁺ 102 5-((4-(ethylamino)-3- ¹H NMR (400 MHz, TFA salt,DMSO) δ 11.86 (br 22 1.99(B) (trifluoromethyl)-1H-pyrrolo[2,3- s, 1H),9.25 (br s, 1H), 8.10 (br s, 1H), b]pyridin-6-yl)amino)-2- 7.66-7.64 (m,1H), 7.53-7.48 (m, 2H), 5.95 methylisoindolin-1-one (s, 1H), 4.84 (br s,1H), 4.39 (s, 2H), 3.29-3.24 (m, 2H), 3.03 (s, 3H), 1.25 (t, J = 7.1 Hz,3H); 390[M + H]⁺ 103 4-(ethylamino)-6-((2-methyl-1- ¹H NMR (400 MHz, TFAsalt, MeOD-d₄)δ 7.78 4.711 oxoisoindol-5-yl)amino)-1H- (d, J = 8.24 Hz,1H), 7.72 (s, 1H), 7.68 (s, pyrrolo[2,3-b]pyridine-3- 1H), 7.49-7.47 (m,1H), 6.01 (s, 1H), 4.51 (s, carbonitrile 2H), 3.45-3.40 (m, 2H), 3.20(s, 3H), 1.38-1.34 (m, 3H); 347[M + H]⁺ 104 6-((6-chloro-2-methyl-1- ¹HNMR (400 MHz, TFA salt, CDCl₃-d₁) δ 8.11 5.058oxoisoindolin-5-yl)amino)-4- (d, J = 1.52 Hz, 1H), 7.98 (s, 1H), 7.92(s, (ethylamino)-1H-pyrrolo[2,3- 1H), 5.88 (b, 1H), 5.51 (s, 1H), 4.39(s, 2H), b]pyridine-3-carbonitrile 3.28-3.25 (m, 2H), 3.22 (s, 3H),1.36-1.32 (m, 3H); 381[M + H]⁺ 105 4-(ethylamino)-6-((6-methoxy- ¹H NMR(400 MHz, Methanol-d₄)δ8.08 (s, 63 5.16 2,2,4-trimethyl-3-oxo-3,4- 1H),7.44 (s, 1H), 6.64 (s, 1H), 5.87 (s, 1H), dihydro-2H- 3.83 (s, 3H), 3.27(s, 3H), 3.27-3.21 (m, 2H), benzo[b][1,4]oxazin-7-yl)amino)- 3.21 (s,3H), 1.33 (s, 6H), 1.24 (t, J = 7.1 1H-pyrrolo[2,3-b]pyridine-3- Hz,3H); 421[M + H]⁺ carbonitrile

<Experimental Example 1> Evaluation 1 of Enzyme Activity InhibitingEffect of the Compound According to the Present Invention

The following experiment was performed to evaluate inhibitory activityof the compound of the present invention against DYRK1A kinase.

Particularly, a substrate was added to a basic reaction buffer (20 mMHepes (pH 7.5), 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA,0.1 mM Na₃VO₄, 2 mM DTT, 1% DMSO), to which cofactors necessary for thereaction were added. Then, DYRK1A kinase was added thereto, followed bymixing well. Each compound of Examples was added thereto by usingacoustic technology (Echo550; nanoliter range). The mixture was left atroom temperature for 20 minutes and then ³³P-ATP (specific activity 10mCi/ml) was added to initiate the reaction. After reacting at roomtemperature for 2 hours, spotting was performed on P81 exchange paper.Upon completion of the reaction, kinase activity was detected using afilter-binding method.

The inhibitory activity of the compounds of Examples 1, 2, 4, 5, 10, 23,27, 53, 56, 57, 59, 60, 61, 63, 65 and 67 against DYRK1A was summarizedin Table 5 below.

The calculated IC₅₀ values of kinase were sorted as follows andpresented in Table 5 below:

-   -   Grade A: less than 10 nM,    -   Grade B: 10˜100 nM, and    -   Grade C: more than 100 nM.

TABLE 5 Example DYRK1A(μM) 1 C 2 A 4 C 5 B 10 A 23 C 27 C 53 B 56 A 57 A59 A 60 B 61 A 63 A 65 A 67 A

As shown in Table 5, when the compounds of the present invention weretreated, the concentration of DYRK1A was significantly reduced to 0.01μM or less. Therefore, since the compounds of the present invention wereexcellent in inhibiting DYRK1A expression, they can be effectively usedfor the treatment or prevention of DYRK1A related disease.

<Experimental Example 2> Evaluation 2 of Enzyme Activity InhibitingEffect of the Compound According to the Present Invention

To evaluate inhibitory activity of the compounds of Examples 2, 54, 55,69, 70, 71, 64, 66, 72, 73, 74, 75, 77, 78, 79, 87, 88, 89, 90, 91, 92,93, 94 and 95 of the present invention against DYRK1A kinase, DYRK1Akinase binding assay was performed using LanthaSceen™ Eu as follows.

First, 10 concentrations (9 concentrations diluted serially by 3× andDMSO) of each compounds were diluted in 1× kinase buffer A (Invitrogen,PV6135) three times the final concentration. The diluted compounds wereadded to a 384-well white assay plate (Corning, 4513) (5

/well).

Then, LanthaScreen™ Eu-anti-GST Antibody (Invitrogen, PV5594) and DYRK1A(Invitrogen, PV3785) were diluted to make the final concentrations of 6nM and 15 nM respectively in 1× kinase buffer A, resulting in thepreparation of antibody/kinase mixed solution. This antibody/kinasemixed solution was added to the assay plate where the diluted compoundwas loaded at the concentration of 5

/well. At this time, the final concentrations of the antibody and theDYRK1A were 2 nM and 5 nM respectively.

Next, kinase tracer 236 solution (Invitrogen, PV5592) was diluted in 1×kinase buffer A to make the concentration of 45 nM. This dilutedsolution was added to the assay plate at the concentration of 5

/well. At this time, the final concentration of kinase tracer 236 was 15nM and K_(d) value of Kinase tracer 236 was determined through tracertitration assay.

Finally, after reacting at room temperature for 1 hour, fluorescence wasmeasured (Excitation 340 nm, Kinase Tracer Emission 665 nm,LanthaScreen™ Eu-anti-GST Antibody Emission 620 nm) using Synergy neo(BioTek). Emission ratio (Kinase Tracer Emission+Antibody Emission) wascalculated based on the measured values, which was presented as adose-response curve. Then, IC₅₀ was calculated.

IC₅₀ values of each compound of Examples 52, 54, 55, 69, 70, 71, 64, 66,72, 73, 74, 75, 77, 78, 79, 87, 88, 89, 90, 91, 92, 93, 94 and 95 weresummarized in Table 6 below.

The calculated IC₅₀ values of kinase were sorted as follows andpresented in Table 6 below:

-   -   Grade A: less than 10 nM,    -   Grade B: 10˜100 nM, and    -   Grade C: more than 100 nM.

TABLE 6 Example IC₅₀(μM) 2 A 54 C 55 C 69 B 70 B 71 C 64 B 66 B 72 C 73B 74 B 75 C 77 C 78 B 79 B 87 B 88 B 89 B 90 B 91 B 92 C 93 C 94 B 95 B

As shown in Table 6, IC₅₀ values of the compounds of the presentinvention for DYRK1A were 0.1 μM or less, indicating that the compoundsof the present invention had excellent activity to inhibit DYRK1Aexpression.

Therefore, since the compounds of the present invention were excellentin inhibiting DYRK1A expression, they can be effectively used for thetreatment or prevention of DYRK1A related disease.

<Experimental Example 3> Calcineurin/NFAT Signaling Inhibitory Activityof the Compound According to the Present Invention

To investigate the intracellular DYRK1A inhibitory effect of thecompounds according to the present invention, DYRK1A high dependentcalcienurin/NFAT signaling experiment was performed.

NFATc transcription factors usually exist as phosphorylated proteins inthe cytoplasm. At this time, as the Ca²⁺ concentration increases, NFATcis dephosphorylated by Ca²⁺ dependent protein phosphatase calcienurin,and NFATc moves into the nucleus.

NFATc in the nucleus can form a transcription complex with the partnerprotein NFATn and can bind to the target gene promoter to induce theexpression of the target gene. At this time, DYRK1A reverselyphosphorylates NFATc to inhibit migration of NFATc to the nucleus,resulting in suppression of the target gene expression.

Based on the facts above, the inhibitory effect of candidate compoundson DYRK1A was measured quantitatively using a luciferase reportercontaining NFAT responsive element (NFAT-RE) in the promoter which isuseful for measuring NFATc transcriptional activity.

Particularly, NFAT-RE-luciferase reporter and DYRK1A were overexpressedin 293T cells. 24 hours later, the cells were treated with IM and PMA(phorbol 12-myristate 13-acetate). 12 hours after the treatment ofcandidate compounds, luciferase activity was measured using One-Gloreagent (Promega).

FIG. 1a is a graph illustrating the luciferase activity of DYRK1Aaffected by the compounds of Examples 53, 54, 55, 56 and 57.

FIG. 1b is a graph illustrating the luciferase activity of DYRK1Aaffected by the compounds of Examples 58, 59, 60, 61, 62, 63, 64, 65,66, 67 and 68.

As shown in FIG. 1a and FIG. 1b , when the compounds of the presentinvention were treated, luciferase activity of DYRK1A was significantlyincreased, compared with when DMSO alone was treated. Therefore, it wasconfirmed that the compounds of the present invention were able toinhibit calcienurin/NFAT signaling efficiently, suggesting that they canbe effectively used for the treatment or prevention of DYRK1A relateddisease.

<Experimental Example 4> Inhibitory Effect of the Compound According tothe Present Invention on the Phosphorylation of Tau

To investigate DYRK1A inhibitory activity of the compounds according tothe present invention, phosphorylation of Tau, which is a representativesubstrate protein of DYRK1A and at the same time a key factor ofAlzheimer's disease and Down syndrome, was confirmed through K1.

Tau is a microtubule related protein. DYRK1A phosphorylates mainlyThr212 of Tau protein, and this phosphorylation has been clearlyobserved in hippocampal tissue of Down syndrome mouse model showingoverexpression of DYRK1A.

Particularly, 293T cells were cultured in a 6-well plate at the densityof 5×10⁵ cells for 12 hours, followed by co-transfection with 1 μg ofeach Tau and DYRK1A expressing DNA. After 24 hours of incubation, thecompound of Example 53 was treated thereto at the concentrations of0.001, 0.01, 0.1 and 1 μM, respectively, followed by culture for 6hours. Then, the cells were recovered and disrupted to obtain a cellextract containing the total protein of 293T cells.

The total protein was developed on SDS-PAGE and transferred to a 0.45 μmpolyvinylidene fluoride transfer membrane; (GE Healthcare, USA),followed by blocking with 5% skim milk. The primary antibodies, anti-Tauantibody (Thermo), anti-pTau (T212) antibody (Invitrogen) andanti-DYRK1A antibody (Santa Cruz) were diluted in tris buffered salinetween-20 (TBST) containing 5% skim milk at the ratio of 1:1000, andtreated to the transfer membrane, followed by reaction for overnight.

Then, the membrane was washed with TBST 4 times for 10 minutes, followedby reaction with secondary antibodies. Upon completion of the reaction,the membrane was washed with TBST 4 times for 10 minutes. Thephosphorylation level of the protein on the transfer membrane wasdetected using WEST-ZOL plus western blotting detection system (iNtRONBiotechnology, USA) and LAS-4000 image analyzer (Fuji Film, Japan).

As for the control, the same experiment was performed using other DYRK1Ainhibitors harmine and CX-4945. As a control for comparing theexpression level, the expressions of hnRNPA1 and GAPDH were confirmed bythe same manner as described above using anti-hnRNP A1 antibody (GideonDreyfuss, University of Pennsylvania, USA) and anti-GAPDH antibody asthe primary antibodies.

FIG. 2a is a photograph illustrating the results of Tau, hnRNPA1 andGAPDH inhibition experiments for each concentration of the compound ofExample 57 in cells.

FIG. 2b is a graph illustrating the Tau inhibition rate at eachconcentration of the compound of Example 57 in cells.

As shown in FIG. 2a and FIG. 2b , when the compound of the presentinvention was treated to the cells, Tau phosphorylation was efficientlyinhibited. Therefore, it was confirmed that the compound of the presentinvention was able to inhibit Tau phosphorylation efficiently,suggesting that it can be effectively used for the treatment orprevention of DYRK1A related disease.

<Experimental Example 5> Evaluation of DYRKIA Inhibitory Effect of theCompound According to the Present Invention In Vivo

1. Observation of Embryos of Neurodevelopmental Disorder DrosophilaModel

To investigate DYRK1A inhibitory effect of the compound of the presentinvention in vivo, embryonic nervous system structure analysis wasperformed using a Drosophila melanogaster model over-expressingminibrain gene. Minibrain is a homologous gene of DYRK1A. MutantDrosophilas lacking the minibrain gene are known to exhibitneurodevelopmental disorder, resulting in a smaller brain phenotype.

To confirm DYRK1A inhibitory effect of the compound of the presentinvention using the Drosophila in vivo model, minibrain (mnb) gene, theDrosophila homologous gene of DYRK1A, was first cloned, and then tissuespecific overexpression was induced using UAS/Gal4 system.

Particularly, Drosophilas transformed with UAS-Minibrain expressionvector were prepared through P-element-mediated germ linetransformation. These transformed Drosophilas were used to performmating with various tissue specific promoter lines.

First, minibrain was over-expressed in the nervous system using theDrosophila nervous system-specific elav-Gal4 promoter line by usingUAS/Gal4 system. F1 generation embryos within 24 hours prior to wakinginto 1^(st) instar larvae were collected and fixed with 4% formalin.Then, synaptobrevin-GFP, a fluorescent protein that can confirm thestructure of the nervous system, was co-expressed and observed with afluorescence confocal microscope to analyze the structure and morphologyof the nervous system.

FIG. 3a is a fluorescent confocal photomicrograph of the wild typeDrosophila embryo,

FIG. 3b is a fluorescent confocal photomicrograph of the Drosophilaembryo with minibrain overexpressing neurodevelopmental abnormality, and

FIG. 3c is a fluorescent confocal photomicrograph of the Drosophilaembryo with minibrain overexpressing neurodevelopmental abnormalitywhich was born by the parents that had been treated with the compound ofExample 57 for 7 days before mating.

Compared with the normal wild type Drosophila embryo shown in FIG. 3a ,dysgenesis of the central and peripheral nervous system was caused bythe overexpression of minibrain, as confirmed in FIG. 3 b.

On the other hand, compared with the Drosophila embryo shown in FIG. 3b, when the compound of the present invention was co-treated, dysgenesisof the peripheral nervous system was significantly reduced, as confirmedin FIG. 3 c.

Therefore, it was confirmed that the compound according to the presentinvention had an excellent inhibitory effect on DYRK1A in vivo. Thus,the compound of the present invention can be effectively used for theprevention or treatment of DYRK1A related disease.

2. Observation of Drosophila Wings Showing Vein DevelopmentalAbnormality

To confirm the DYRK1A inhibitory effect of the compound according to thepresent invention in vivo, wings of the Drosophila model over-expressingminibrain gene specifically in wings were observed.

First, in order to produce Drosophila over-expressing minibrainspecifically in wings, the UAS-Minibrain transformed Drosophila wasmated with the wing specific promoter MS1096-Gal4 transformedDrosophila, resulting in the production of F1 generation.

Next, the effect of improving wing defects was confirmed to verify theDYRK1A inhibitory effect of the compound according to the presentinvention using the Drosophila DYRK1A/minibrain inhibitor discoverymodel. A medium supplemented with the compound at the concentration of10 μM was prepared, in which embryos of Drosophila over-expressingminibrain specifically in wings were raised, followed by investigationof wing phenotype.

FIG. 4a is a photograph of wings of the control group and the Drosophilaover-expressing minibrain specifically in the wings, and

FIG. 4b is a graph illustrating the inhibitory effect of the compoundsof Examples 58, 59, 60, 61, 62, 63, 64, 65, 66 and 67 of the presentinvention on the wing vein developmental abnormality.

As shown in FIG. 4a , at least 90% of F1 generation (MS1096>2×mnb)displayed developmental abnormality in L5 vein (short wing veinphenotype).

As shown in FIG. 4b , it was confirmed that the compounds according tothe present invention showed excellent inhibitory effect on the wingvein developmental abnormality. In particular, the compounds of Examples58 (47.9%), 62 (47.7%) and 63 (43.8%) were confirmed to inhibit the wingvein developmental abnormality significantly.

3. Observation of Mouse Pancreatic β-Cell Proliferation

It is known that when human β-cells are treated with harmine thatinhibits DYRK1A, the proliferation of B-cells is promoted by increasingthe transcription factor activity by inhibiting the phosphorylation ofNFAT known as a phosphorylation substrate of DYRK1A. In order to confirmthe DYRK1A inhibitory effect of the compound of the present invention invivo, an experiment was performed to examine the mouse pancreatic β-cellcell proliferation.

Particularly, pancreatic Langerhans islet tissues were extracted fromthe mouse at 8 weeks old, followed by culture in RPMI1640 mediumsupplemented with 10% FCS (fetal calves serum), 5.5 mM glucose and 1%penicillin-streptomycin for 24 hours.

Next, in order to separate B-cells as single cells from the Langerhansislet, cells were washed twice with PBS, followed by centrifugation. Thecollected cells were left in the medium supplemented with 1 mg/ml oftrypsin for 10 minutes at 37° C. The cells were shaken using a pipetteevery 10 seconds for 5 minutes. Trypsin reaction was terminated byadding RPMI1640 containing 10% FCS (fetal calves serum), 5.5 mM glucoseand 1% penicillin-streptomycin, followed by centrifugation to collectsingle cells.

Then, the single cells were loaded on the laminin-coated cover glass andstabilized for 24 hours. The cells were cultured in the mediumcontaining the compound of the present invention for 72 hours.Immunofluorescence staining was performed using Ki-67 antibody which isuseful for confirming cell division and insulin antibody which is usefulfor confirming R-cells. The cells double-stained with Ki-67/insulin werecounted under Olympus F-1000 confocal fluorescence microscope toinvestigate cell proliferation.

FIG. 5a is an immunofluorescent staining confocal fluorescencephotomicrograph of the control group,

FIG. 5b is an immunofluorescent staining confocal fluorescencephotomicrograph of the mouse treated with harmine,

FIG. 5c is an immunofluorescent staining confocal fluorescencephotomicrograph of the mouse treated with the compound of Example 57,and

FIG. 5d is a graph illustrating the cell number of each mouse model.

As shown in FIG. 5a and FIG. 5b , when harmine was treated, cellproliferation was active.

As shown in FIG. 5c , when the compound of Example 57 was treated, cellproliferation was also active.

Further, as shown in FIG. 5d , it was confirmed by quantitativemeasurement of cells that the treatment of the compound of Example 57increased the cell number as much as 5 times.

It was confirmed by each in vivo experiment above that the compound ofthe present invention was able to inhibit the expression of DYRK1Aefficiently.

Therefore, since the compound of the present invention inhibited theexpression of DYRK1A efficiently, it can be effectively used for thetreatment and prevention of DYRK1A related disease.

<Experimental Example 6> Evaluation of Kinase Inhibitory Activity of theCompound According to the Present Invention

The following experiment was performed to evaluate the activity of thecompounds of the present invention to inhibit many enzymes.

Particularly, the compounds of Examples 18 and 57 were selected amongall of those compounds of the present invention. DiscoverX Co. was askedto measure the enzyme (kinase) selectivity, and the experiment wasperformed using scanMAX™ Kinase assay panel.

At this time, the concentration of the drug treated to each enzyme was 1uM in DMSO and the control percentage (% control) was determined by thefollowing Equation 1. The results are shown in Table 7 below.

(Example Compound−Positive Control)/(Negative

Control−Positive Control)×100   [Equation 1]

Herein, the positive control indicates the compound showing the %control of 0%, and the negative control indicates DMSO showing the %control of 100%. The enzyme selectivity in the present invention isdefined as follows: When the % control for each enzyme is less than 35%(<35%), it is judged that the compound has the activity to thecorresponding enzyme.

TABLE 7 Example 18 Example 57 AAK1 69 54 ABL1(E255K) - phosphorylated 7784 ABL1(F317I) - nonphosphorylated 89 96 ABL1(F317I) - phosphorylated 80100 ABL1(F317L) - nonphosphorylated 95 86 ABL1(F317L) - phosphorylated100 100 ABL1(H396P) - nonphosphorylated 89 68 ABL1(H396P) -phosphorylated 85 100 ABL1(M351T) - phosphorylated 100 98 ABL1(Q252H) -nonphosphorylated 95 54 ABL1(Q252H) - phosphorylated 100 100ABL1(T315I) - nonphosphorylated 96 100 ABL1(T315I) - phosphorylated 10096 ABL1(Y253F) - phosphorylated 89 100 ABL1-nonphosphorylated 97 51ABL1-phosphorylated 87 61 ABL2 93 98 ACVR1 92 88 ACVR1B 88 82 ACVR2A 10099 ACVR2B 100 98 ACVRL1 80 89 ADCK3 86 89 ADCK4 100 75 AKT1 100 97 AKT287 90 AKT3 96 96 ALK 2.7 2.5 ALK(C1156Y) 2.4 3.5 ALK(L1196M) 13 14AMPK-alpha1 92 75 AMPK-alpha2 100 98 ANKK1 78 100 ARK5 94 94 ASK1 79 77ASK2 82 92 AURKA 94 83 AURKB 73 81 AURKC 92 95 AXL 98 100 BIKE 90 85 BLK99 73 BMPR1A 74 80 BMPR1B 85 100 BMPR2 44 84 BMX 75 89 BRAF 83 98BRAF(V600E) 87 94 BRK 95 94 BRSK1 94 94 BRSK2 96 79 BTK 99 100 BUB1 7699 CAMK1 62 78 CAMK1B 34 81 CAMK1D 31 73 CAMK1G 71 63 CAMK2A 72 72CAMK2B 73 80 CAMK2D 82 47 CAMK2G 77 72 CAMK4 76 88 CAMKK1 70 59 CAMKK252 49 CASK 76 88 CDC2L1 100 90 CDC2L2 86 88 CDC2L5 100 92 CDK11 98 67CDK2 100 100 CDK3 97 94 CDK4 100 100 CDK4-cyclinD1 100 95 CDK4-cyclinD3100 100 CDK5 100 86 CDK7 55 53 CDK8 100 90 CDK9 100 85 CDKL1 89 63 CDKL2100 90 CDKL3 100 61 CDKL5 100 91 CHEK1 100 91 CHEK2 4.1 47 CIT 71 66CLK1 1.9 1.1 CLK2 8.5 3.3 CLK3 73 35 CLK4 4 23 CSF1R 73 72CSF1R-autoinhibited 51 83 CSK 93 76 CSNK1A1 8.2 51 CSNK1A1L 3.1 71CSNK1D 5.3 30 CSNK1E 0.6 51 CSNK1G1 43 88 CSNK1G2 27 86 CSNK1G3 7.1 89CSNK2A1 83 100 CSNK2A2 97 80 CTK 100 84 DAPK1 16 70 DAPK2 16 71 DAPK3 1486 DCAMKL1 85 86 DCAMKL2 77 79 DCAMKL3 84 88 DDR1 98 98 DDR2 98 91 DLK79 100 DMPK 81 100 DMPK2 85 96 DRAK1 56 67 DRAK2 27 69 DYRK1A 2 0.4DYRK1B 4 1.8 DYRK2 14 27 EGFR 100 59 EGFR(E746-A750del) 83 98EGFR(G719C) 95 91 EGFR(G719S) 80 92 EGFR(L747-E749del, A750P) 100 94EGFR(L747-S752del, P753S) 92 97 EGFR(L747-T751del, Sins) 100 97EGFR(L858R) 100 100 EGFR(L858R, T790M) 81 73 EGFR(L861Q) 85 94EGFR(S752-I759del) 99 75 EGFR(T790M) 100 88 EIF2AK1 92 99 EPHA1 91 78EPHA2 97 83 EPHA3 93 100 EPHA4 98 94 EPHA5 99 85 EPHA6 98 87 EPHA7 94100 EPHA8 85 100 EPHB1 95 94 EPHB2 87 100 EPHB3 93 85 EPHB4 100 88 EPHB678 99 ERBB2 99 73 ERBB3 97 100 ERBB4 85 82 ERK1 100 98 ERK2 94 74 ERK385 94 ERK4 98 93 ERK5 20 50 ERK8 99 93 ERN1 24 61 FAK 78 77 FER 62 67FES 89 87 FGFR1 87 87 FGFR2 85 72 FGFR3 93 94 FGFR3(G697C) 88 78 FGFR480 92 FGR 100 78 FLT1 46 94 FLT3 83 100 FLT3(D835H) 89 100 FLT3(D835V)74 92 FLT3(D835Y) 82 88 FLT3(ITD) 92 79 FLT3(ITD, D835V) 100 100FLT3(ITD, F691L) 46 84 FLT3(K663Q) 84 94 FLT3(N841I) 89 85 FLT3(R834Q)92 100 FLT3-autoinhibited 82 92 FLT4 100 99 FRK 94 92 FYN 78 87 GAK 1541 GCN2(Kin.Dom.2, S808G) 97 91 GRK1 81 94 GRK2 71 95 GRK3 58 100 GRK4100 100 GRK7 96 84 GSK3A 100 90 GSK3B 97 74 HASPIN 7.6 70 HCK 85 88HIPK1 63 54 HIPK2 68 100 HIPK3 74 71 HIPK4 100 86 HPK1 76 91 HUNK 57 51ICK 84 100 IGF1R 74 71 IKK-alpha 44 100 IKK-beta 77 100 IKK-epsilon 9696 INSR 36 48 INSRR 24 60 IRAK1 79 100 IRAK3 84 79 IRAK4 99 100 ITK 8797 JAK1(JH1domain-catalytic) 100 97 JAK1(JH2domain-pseudokinase) 82 45JAK2(JH1domain-catalytic) 70 100 JAK3(JH1domain-catalytic) 54 100 JNK1 040 JNK2 0.1 52 JNK3 0 52 KIT 49 91 KIT(A829P) 99 100 KIT(D816H) 80 96KIT(D816V) 82 83 KIT(L576P) 77 100 KIT(V559D) 33 77 KIT(V559D, T670I) 4878 KIT(V559D, V654A) 97 84 KIT-autoinhibited 66 100 LATS1 97 94 LATS2 26100 LCK 96 90 LIMK1 92 99 LIMK2 90 99 LKB1 62 92 LOK 91 84 LRRK2 1.1 48LRRK2(G2019S) 0.6 27 LTK 6.2 20 LYN 90 100 LZK 100 100 MAK 92 95 MAP3K190 79 MAP3K15 53 100 MAP3K2 79 100 MAP3K3 70 75 MAP3K4 96 79 MAP4K2 61100 MAP4K3 93 91 MAP4K4 100 100 MAP4K5 99 100 MAPKAPK2 21 51 MAPKAPK5 43100 MARK1 84 82 MARK2 89 93 MARK3 100 92 MARK4 80 76 MAST1 93 66 MEK1 19100 MEK2 26 100 MEK3 4.3 81 MEK4 0 98 MEK5 77 99 MEK6 53 72 MELK 62 69MERTK 100 91 MET 100 100 MET(M1250T) 100 100 MET(Y1235D) 100 85 MINK 55100 MKK7 89 93 MKNK1 93 100 MKNK2 60 95 MLCK 87 78 MLK1 100 100 MLK2 7277 MLK3 99 80 MRCKA 100 95 MRCKB 92 100 MST1 99 76 MST1R 81 70 MST2 95100 MST3 88 84 MST4 81 100 MTOR 86 88 MUSK 97 100 MYLK 6 7.8 MYLK2 72 85MYLK4 88 83 MYO3A 71 70 MYO3B 73 83 NDR1 69 89 NDR2 95 80 NEK1 100 81NEK10 73 100 NEK11 100 100 NEK2 100 94 NEK3 87 93 NEK4 86 99 NEK5 92 91NEK6 97 84 NEK7 89 85 NEK9 91 89 NIK 25 82 NIM1 81 100 NLK 84 84 OSR1 4182 p38-alpha 100 83 p38-beta 77 76 p38-delta 99 85 p38-gamma 77 77 PAK192 73 PAK2 82 40 PAK3 93 83 PAK4 88 93 PAK6 98 78 PAK7 80 100 PCTK1 9883 PCTK2 100 98 PCTK3 86 86 PDGFRA 77 100 PDGFRB 76 92 PDPK1 99 86PFCDPK1(P. falciparum) 72 98 PFPK5(P. falciparum) 98 98 PFTAIRE2 79 94PFTK1 89 95 PHKG1 16 26 PHKG2 12 23 PIK3C2B 100 78 PIK3C2G 92 100 PIK3CA100 87 PIK3CA(C420R) 87 100 PIK3CA(E542K) 96 100 PIK3CA(E545A) 100 77PIK3CA(E545K) 92 73 PIK3CA(H1047L) 85 100 PIK3CA(H1047Y) 71 73PIK3CA(I800L) 100 69 PIK3CA(M1043I) 100 99 PIK3CA(Q546K) 100 100 PIK3CB89 100 PIK3CD 100 100 PIK3CG 100 87 PIK4CB 80 100 PIKFYVE 99 77 PIM1 5994 PIM2 96 98 PIM3 78 78 PIP5K1A 100 88 PIP5K1C 67 69 PIP5K2B 87 100PIP5K2C 16 71 PKAC-alpha 70 100 PKAC-beta 66 92 PKMYT1 90 96 PKN1 85 71PKN2 92 92 PKNB(M. tuberculosis) 82 100 PLK1 41 100 PLK2 81 90 PLK3 7998 PLK4 40 47 PRKCD 75 87 PRKCE 77 64 PRKCH 95 99 PRKCI 76 63 PRKCQ 9496 PRKD1 14 73 PRKD2 2 83 PRKD3 9.6 78 PRKG1 64 98 PRKG2 58 85 PRKR 9593 PRKX 92 80 PRP4 100 91 PYK2 60 76 QSK 92 87 RAF1 97 72 RET 100 100RET(M918T) 99 100 RET(V804L) 97 91 RET(V804M) 99 95 RIOK1 94 94 RIOK2 63100 RIOK3 98 96 RIPK1 94 92 RIPK2 86 94 RIPK4 69 95 RIPK5 18 79 ROCK19.1 100 ROCK2 7.8 100 ROS1 83 69 RPS6KA4(Kin.Dom.1-N-terminal) 100 100RPS6KA4(Kin.Dom.2-C-terminal) 0.3 100 RPS6KA5(Kin.Dom.1-N-terminal) 100100 RPS6KA5(Kin.Dom.2-C-terminal) 10 83 RSK1(Kin.Dom.1-N-terminal) 73 76RSK1(Kin.Dom.2-C-terminal) 64 77 RSK2(Kin.Dom.1-N-terminal) 78 96RSK2(Kin.Dom.2-C-terminal) 100 100 RSK3(Kin.Dom.1-N-terminal) 92 75RSK3(Kin.Dom.2-C-terminal) 12 82 RSK4(Kin.Dom.1-N-terminal) 81 100RSK4(Kin.Dom.2-C-terminal) 71 80 S6K1 70 100 SBK1 86 90 SGK 64 100SgK110 100 96 SGK2 64 100 SGK3 79 100 SIK 100 90 SIK2 87 95 SLK 95 80SNARK 57 100 SNRK 100 100 SRC 100 100 SRMS 80 96 SRPK1 89 85 SRPK2 100100 SRPK3 96 100 STK16 60 64 STK33 17 16 STK35 85 98 STK36 98 98 STK3926 43 SYK 66 68 TAK1 59 79 TAOK1 82 100 TAOK2 77 85 TAOK3 94 100 TBK1 7685 TEC 100 92 TESK1 90 79 TGFBR1 100 69 TGFBR2 100 97 TIE1 88 100 TIE282 89 TLK1 100 73 TLK2 98 88 TNIK 89 94 TNK1 81 100 TNK2 92 86 TNNI3K 91100 TRKA 86 100 TRKB 100 100 TRKC 93 100 TRPM6 87 97 TSSK1B 34 53 TSSK330 91 TTK 8.9 67 TXK 99 85 TYK2(JH1domain-catalytic) 59 100TYK2(JH2domain-pseudokinase) 67 100 TYRO3 80 96 ULK1 78 94 ULK2 67 93ULK3 95 83 VEGFR2 63 95 VPS34 96 79 VRK2 87 100 WEE1 100 100 WEE2 91 96WNK1 93 100 WNK2 91 100 WNK3 82 100 WNK4 79 100 YANK1 100 100 YANK2 10094 YANK3 96 71 YES 90 83 YSK1 99 73 YSK4 6.7 100 ZAK 96 87 ZAP70 38 100

As shown in Table 7, the compounds of the present invention demonstratedsmaller % control than 35% for such kinases as ALK, ALK (C1156Y), ALK(L1196M), CAMK1B, CAMK1D, CHEK2, CLK1, CLK2, CLK3, CLK4, CSNK1A1,CSNK1A1L, CSNK1D, CSNK1E, CSNK1G2, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK2,DYRK1A, DYRKIB, DYRK2, ERK5, ERN1, GAK, HASPIN, INSRR, JNK1, JNK2, JNK3,KIT (V559D), LATS2, LRRK2, LRRK2 (G2019S), LTK, MAPKAPK2, MEK1, MEK2,MEK3, MEK4, MYLK, NIK, PHKG1, PHKG2, PIP5K2C, PRKD1, PRKD2, PRKD3,RIPK5, ROCK1, ROCK2, RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.2-C-terminal), STK33, STK39,TSSK1B, TSSK3, TTK and YSK4. The result above indicates that thecompounds of the present invention have the activity of inhibiting thelisted enzymes above, confirming the usability of the compounds of theinvention for the disease relating to the enzymes listed above.

Therefore, the pyrrolo-pyridine derivative compounds of the presentinvention can be effectively used as a pharmaceutical composition forthe treatment or prevention of ALK, ALK (C1156Y), ALK (L1196M), CAMK1B,CAMK1D, CHEK2, CLK1, CLK2, CLK3, CLK4, CSNK1A1, CSNK1A1L, CSNK1D,CSNK1E, CSNK1G2, CSNK1G3, DAPK1, DAPK2, DAPK3, DRAK2, DYRK1A, DYRKIB,DYRK2, ERK5, ERN1, GAK, HASPIN, INSRR, JNK1, JNK2, JNK3, KIT (V559D),LATS2, LRRK2, LRRK2 (G2019S), LTK, MAPKAPK2, MEK1, MEK2, MEK3, MEK4,MYLK, NIK, PHKG1, PHKG2, PIP5K2C, PRKD1, PRKD2, PRKD3, RIPK5, ROCK1,ROCK2, RPS6KA4 (Kin.Dom.2-C-terminal), RPS6KA5 (Kin.Dom.2-C-terminal),RSK3 (Kin.Dom.2-C-terminal), STK33, STK39, TSSK1B, TSSK3, TTK or YSK4related disease.

<Experimental Example 7> Evaluation of Tau Phosphorylation InhibitoryActivity of the Compound of the Invention in the Alzheimer's DiseaseAnimal Model

The following experiment was performed to investigate the effect of thecompound of Example 57 of the present invention on tau phosphorylationin the Alzheimer's disease animal model.

Particularly, 5×FAD mice were administered with the compound of Example57 of the present invention (20 mg/kg) or vehicle (non-treated group)via i.p. injection every day for 2 weeks. 2 weeks later,immunohistochemistry was performed using AT180, one of Tauphosphorylation antibodies, and as a result confocal microscope imageswere obtained. Quantitative analysis with the images was performed usingimage j software. The results are shown in FIGS. 6a -6 e.

FIGS. 6a-6e present the results of the evaluation of Tau phosphorylationinhibitory activity of the compound in the Alzheimer's disease animalmodel. FIG. 6a : immunofluorescent staining confocal fluorescencephotomicrograph of the cerebral cortex of the Alzheimer's disease animalmodel treated with vehicle (untreated group) or the compound of Example57 (DAPI: immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), AT180: image obtained byimmunohistochemistry using AT180 antibody, Merge: image obtained byoverlapping DAPI and AT180 images, Enlarge: image obtained by enlargingAT180 image), FIG. 6b : graph illustrating the immunoreactivity of AT180in the cerebral cortex of the Alzheimer's disease animal model treatedwith vehicle (untreated group) or the compound of Example 57, FIG. 6c :immunofluorescent staining confocal fluorescence photomicrograph of thecerebral cortex of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57 (DAPI:immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), AT180: image obtained byimmunohistochemistry using AT180 antibody, Enlarge (CA1): enlarged imageof CA1 (cornus aminus, the region where the hippocampus begins andlong-term memory is formed) of the hippocampus of AT180 image, Enlarge(DG): enlarged image of DG (dentate gyrus, the region where thehippocampus ends and new memory is formed) of the hippocampus of AT180image, FIG. 6d : graph illustrating the immunoreactivity of AT180 in theCA1 (cornus aminus) of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57, FIG. 6e : graphillustrating the immunoreactivity of AT180 in the DG (dentate gyrus) ofthe Alzheimer's disease animal model treated with vehicle (untreatedgroup) or the compound of Example 57

As shown in FIGS. 6a-6e , it was confirmed that the immunoreactivity ofAT180 was significantly reduced in the hippocampus of the miceintraperitoneally administered with 20 mg/kg of the compound of Example57 of the present invention (vehicle vs #57 (20 mg/kg): *p<0.05,**p<0.001). However, there was no significant change in theimmunoreactivity of AT180 in the cerebral cortex region, compared withthe group treated with vehicle (non-treated group).

From the above results, it was confirmed that the compound representedby chemical formula 1 of the present invention was able to alleviate thesymptoms of Alzheimer's disease.

<Experimental Example 8> Evaluation of Changes of DYRK1A Protein by theCompound of the Invention in the Alzheimer's Disease Animal Model

The following experiment was performed to investigate the effect of thecompound of Example 57 of the present invention on the target geneDYRK1A protein in the Alzheimer's disease animal model.

Particularly, 5×FAD mice were administered with the compound of Example57 of the present invention (20 mg/kg) or vehicle (non-treated group)via i.p. injection every day for 2 weeks. 2 weeks later,immunohistochemistry was performed using DYRK1A, and as a resultconfocal microscope images were obtained. Quantitative analysis with theimages was performed using image j software. The results are shown inFIGS. 7a -7 e.

FIGS. 7a-7e present the changes of DYRK1A protein by the compound of thepresent invention in the Alzheimer's disease animal model. FIG. 7a :immunofluorescent staining confocal fluorescence photomicrograph of thecerebral cortex of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57 (DAPI:immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), DYRK1A: image obtained byimmunohistochemistry using DYRK1A protein, Merge: image obtained byoverlapping DAPI and DYRK1A images, Enlarge: image obtained by enlargingDYRK1A image), FIG. 7b : graph illustrating the immunoreactivity ofDYRK1A in the cerebral cortex of the Alzheimer's disease animal modeltreated with vehicle (untreated group) or the compound of Example 57,FIG. 7c : immunofluorescent staining confocal fluorescencephotomicrograph of the cerebral cortex of the Alzheimer's disease animalmodel treated with vehicle (untreated group) or the compound of Example57 (DAPI: immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), DYRK1A: image obtained byimmunohistochemistry using DYRK1A protein, Enlarge (CA1): enlarged imageof CA1 (cornus aminus, the region where the hippocampus begins andlong-term memory is formed) of the hippocampus of DYRK1A image, Enlarge(DG): enlarged image of DG (dentate gyrus, the region where thehippocampus ends and new memory is formed) of the hippocampus of DYRK1Aimage, FIG. 7d : graph illustrating the immunoreactivity of DYRK1A inthe CA1 (cornus aminus) of the Alzheimer's disease animal model treatedwith vehicle (untreated group) or the compound of Example 57, FIG. 7e :graph illustrating the immunoreactivity of DYRK1A in the DG (dentategyrus) of the Alzheimer's disease animal model treated with vehicle(untreated group) or the compound of Example 57

As shown in FIGS. 7a-7e , it was confirmed that the immunoreactivity ofDYRK1A was significantly reduced not only in the cerebral cortex butalso in the CA1 and DG regions of the hippocampus in the miceintraperitoneally administered with 20 mg/kg of the compound of Example57 of the present invention (vehicle vs #57 (20 mg/kg): ***p<0.0001).

From the above results, it was confirmed that the compound representedby chemical formula 1 of the present invention was able to alleviate thesymptoms of Alzheimer's disease.

<Experimental Example 9> Evaluation of Changes of Amyloid Plaque by theCompound of the Invention in the Alzheimer's Disease Animal Model

The following experiment was performed to investigate the effect of thecompound of Example 57 of the present invention on amyloid plaque, oneof key factors causing Alzheimer's disease, in the Alzheimer's diseaseanimal model.

Particularly, 5×FAD mice were administered with the compound of Example57 of the present invention (20 mg/kg) or vehicle (non-treated group)via i.p. injection every day for 2 weeks. 2 weeks later,immunohistochemistry was performed using 4G8 antibody capable ofdetecting amyloid plaque, and as a result confocal microscope imageswere obtained. Quantitative analysis with the images was performed usingimage j software. The results are shown in FIGS. 8a -8 d.

FIGS. 8a-8d present the changes of amyloid plaque by the compound ofExample 57 in the Alzheimer's disease animal model. FIG. 8a :immunofluorescent staining confocal fluorescence photomicrograph of thecerebral cortex and the hippocampus of the Alzheimer's disease animalmodel treated with vehicle (untreated group) or the compound of Example57 (DAPI: immunofluorescence image staining with DAPI(4′,6-diamidino-2-phenylindol), 4G8: image obtained byimmunohistochemistry using 4G8 antibody, Merge: image obtained byoverlapping DAPI and 4G8 images), FIG. 8b : graph illustrating thechanges in the number of amyloid plaque of 4G8 in the cerebral cortex ofthe Alzheimer's disease animal model treated with vehicle (untreatedgroup) or the compound of Example 57, FIG. 8c : graph illustrating thechanges in the number of amyloid plaque of 4G8 in the CA1 (cornusaminus) of the Alzheimer's disease animal model treated with vehicle(untreated group) or the compound of Example 57, FIG. 8d : graphillustrating the changes in the number of amyloid plaque of 4G8 in theDG (dentate gyrus) of the Alzheimer's disease animal model treated withvehicle (untreated group) or the compound of Example 57

As shown in FIGS. 8a-8d , it was confirmed that the number of amyloidplaque was significantly reduced not only in the cerebral cortex butalso in the DG region of the hippocampus in the mice intraperitoneallyadministered with 20 mg/kg of the compound of Example 57 of the presentinvention (vehicle vs 20 mg/kg: ***p<0.0001). However, in the CA regionof the hippocampus, the number of amyloid plaque was not much reduced,compared with the non-treated group.

From the above results, it was confirmed that the compound representedby chemical formula 1 of the present invention was able to alleviate thesymptoms of Alzheimer's disease.

<Experimental Example 10> Evaluation of Short Term Cognitive ImprovementEffect of the Compound of the Invention Through Behavioral Test (Y-Maze)

The following experiment was performed to investigate whether thecompound of Example 57 of the present invention was able to improveshort term cognitive function in the Alzheimer's disease animal model.

Particularly, 5×FAD mice were administered with the compound of Example57 of the present invention (20 mg/kg) or vehicle (non-treated group)via i.p. injection every day for 2 weeks. Then, the mice were placed inY-maze composed of three arms abutting 120°, and each arm was liftedsequentially for five minutes to calculate the number of alternationtriplets to see how well the mice remembered where they visited.

The equipment used for Y-maze test is composed of three arms. The lengthof each arm was 42 cm, the width thereof was 3 cm and the height was 12cm. The angle of contact between the three arms is 120°. Allexperimental devices were made of black polyvinyl plastic. Each arm wasassigned with A, B and C. A test mouse was carefully located in one armand let move freely for 8 minutes. Then, the arm which the test mouseentered was recorded. At this time, the ‘enter’ means the case when themouse tail was completely in. If the mouse entered an arm where it hadalready visited, the case was also recorded. If the mouse entered threedifferent arms one by one (actual alternation), one point was given.Alternation behavior was defined by that the mouse entered threedifferent arms stepwise, which was calculated by the following equation.FIG. 9a shows the schematic diagram of Y-maze, and FIG. 9b presents thecalculation results.

[alternation behavior (%)=actual alternation/*maximum

alternation×100]*maximum alternation: total entries−2

FIGS. 9a and 9b present the results of evaluating short term cognitiveimprovement effect through behavioral tests. FIG. 9a : schematic diagramof Y-maze to measure the short term memory of the brain, FIG. 9b : graphillustrating the behavioral changes of the mouse tested with Y-maze

As shown in FIGS. 9a and 9b , short term memory was declined in thenon-treated group (5×FAD mice were administered with vehicle throughi.p. injection), compared with the wild type group (wild type mice wereadministered with vehicle through i.p. injection), confirmed byalteration behavior test above. On the other hand, the experimentalgroup (5×FAD mice were administered with the compound of Example 57 ofthe present invention at the concentration of 20 mg/kg through i.p.injection) showed improved short term memory, compared with thenon-treated group (5×FAD: vehicle vs 20 mg/kg:**p<0.01).

From the above results, it was confirmed that the compound representedby chemical formula 1 of the present invention was able to improve shortterm cognitive decline caused by Alzheimer's disease.

<Experimental Example 11> Evaluation of Long Term Cognitive ImprovementEffect of the Compound of the Invention Through Behavioral Test—NovelObject Recognition Test

The following experiment was performed to investigate whether thecompound of Example 57 of the present invention was able to improve longterm cognitive function in the Alzheimer's disease animal model. Novelobject recognition test is an experiment to test the memory ofperception of an object. Mice were let to see two identical objects.After a certain period of time had passed (several hours˜a week), themice were let to see a novel object together with the object previouslypresented. Then, how much those mice were interested in the novel objectand studied it was evaluated, leading to the evaluation of long termmemory of the previous object.

Particularly, 5×FAD mice were administered with the compound of Example57 of the present invention (20 mg/kg) or vehicle (non-treated group)via i.p. injection every day for 2 weeks. Two objects which were thesame in the shape and in the size (F, F) were placed in a specificcorner of the open field box (42×42×42 cm) made that the outside is notinvisible from the inside, and a test mouse was started from the centerof the box. Then, the number and time of the test mouse touching thosetwo objects were recorded for 5 minutes (Acquisition). 24 hours later,one of those two objects was replaced with a new one (F, N). The numberand time of access to the original object (F) and the new object (N)were recorded and digitized (Discrimination). Preference for the object(p) was calculated by (time to approach to a certain object)/(total timeto approach to two objects). FIG. 10a presents the schematic diagram ofnovel object recognition test, and FIGS. 10b and 10c present thecalculation results.

FIGS. 10a-10c present the results of evaluating long term cognitiveimprovement effect through behavioral tests. FIG. 10a : schematicdiagram of novel object recognition test to measure the long term memoryof the brain and equation to calculate novel object preference, FIG. 10b: graph illustrating the object preference of the test mouse evaluatedby novel object recognition test, FIG. 10c : graph illustrating thenovel object preference of the test mouse evaluated by novel objectrecognition test As shown in FIGS. 10a-10c , in the stage ofdiscrimination, long term memory measured by preference for the newobject was declined in the non-treated group (5×FAD mice wereadministered with vehicle through i.p. injection), compared with thewild type group (wild type mice were administered with vehicle throughi.p. injection). On the other hand, the experimental group (5×FAD micewere administered with the compound of Example 57 of the presentinvention at the concentration of 20 mg/kg through i.p. injection)showed improved long term memory, compared with the non-treated group(5×FAD: vehicle vs 20 mg/kg: **p<0.01).

From the above results, it was confirmed that the compound representedby chemical formula 1 of the present invention was able to improve longterm cognitive decline caused by Alzheimer's disease.

The compound represented by chemical formula 1 of the present invention,the optical isomer thereof or the pharmaceutically acceptable saltthereof was confirmed to have excellent activity to inhibit DYRK1Akinase in Experimental Examples 1 and 2. In addition, the compoundrepresented by chemical formula 1 of the present invention, the opticalisomer thereof or the pharmaceutically acceptable salt thereof wasconfirmed to have excellent activity to inhibit DYRK1A phosphorylationat the cellular level in Experimental Example 3. It was also confirmedin Experimental Example 4 that the compound represented by chemicalformula 1 of the present invention, the optical isomer thereof or thepharmaceutically acceptable salt thereof was excellent in inhibitingphosphorylation of Tau, an important factor of Down syndrome. Further,it was also confirmed in Experimental Example 5 that the compoundrepresented by chemical formula 1 of the present invention, the opticalisomer thereof or the pharmaceutically acceptable salt thereof hadDYRK1A kinase activity inhibiting effect in vivo.

The compound represented by chemical formula 1 of the present invention,the optical isomer thereof or the pharmaceutically acceptable saltthereof was confirmed to have excellent activity to inhibit Tauphosphorylation in the Alzheimer's disease animal model in ExperimentalExample 7. It was also confirmed in Experimental Example 8 that thecompound represented by chemical formula 1 of the present invention, theoptical isomer thereof or the pharmaceutically acceptable salt thereofwas excellent in inhibiting DYRK1A protein activity. In ExperimentalExample 9, the compound represented by chemical formula 1 of the presentinvention, the optical isomer thereof or the pharmaceutically acceptablesalt thereof was confirmed to reduce amyloid plaque, one of causes ofAlzheimer's disease. In Experimental Example 10, the compoundrepresented by chemical formula 1 of the present invention, the opticalisomer thereof or the pharmaceutically acceptable salt thereof wasconfirmed to improve the short term cognitive decline caused byAlzheimer's disease, and also confirmed to improve the long termcognitive decline caused by Alzheimer's disease in Experimental Example11.

Therefore, a pharmaceutical composition and a health functional foodcomposition comprising the compound represented by chemical formula 1 ofthe present invention, the optical isomer thereof or thepharmaceutically acceptable salt thereof can be effectively used for thetreatment or prevention of DYRK1A related disease. In particular, theycan be effectively used for the prevention, treatment or amelioration ofAlzheimer's disease, dementia or Alzheimer's dementia.

INDUSTRIAL APPLICABILITY

The compound represented by chemical formula 1 of the present invention,the optical isomer thereof or the pharmaceutically acceptable saltthereof can be effectively used for the treatment or prevention ofprotein kinase related disease. In particular, it can be effectivelyused for the prevention, treatment or amelioration of Alzheimer'sdisease, dementia or Alzheimer's dementia.

1. A method of treating a subject having a disease selected from thegroup consisting of cancer and metabolic disease, comprisingadministering an effective amount of a compound to the subject, whereinthe compound is represented by chemical formula 1:

the optical isomer thereof or a pharmaceutically acceptable saltthereof, or a composition thereof, wherein: Z is cyano (—CN); orstraight or branched C₁-C₃ alkyl substituted with one or more halogens;X is —NR^(a)—, —O— or —S—, wherein R^(a) is hydrogen or straight orbranched C₁-C₁₀ alkyl, wherein, the alkyl can be substituted with one ormore substituents selected from the group consisting of —OH and C₁-C₃alkoxy; R¹ is straight or branched C₁-C₁₀ alkyl, C₃-C₈ cycloalkyl orC₆₋₁₄ aryl, wherein, the alkyl or cycloalkyl can be substituted with oneor more substituents selected from the group consisting of —OH, and,straight or branched C₁-C₃ alkyl and C₁-C₃ alkoxy, and the aryl can besubstituted with one or more substituents selected from the groupconsisting of straight or branched C₁-C₃ alkyl and straight or branchedC₁-C₃ alkoxy, nonsubstituted or substituted with one or more halogens;or, R^(a) can form nonsubstituted or substituted 5-8 memberedheterocycloalkyl containing one or more heteroatoms selected from thegroup consisting of N, O and S along with R¹ and nitrogen atom to whichthey are attached, and the substituted heterocycloalkyl can besubstituted with one or more substituents selected from the groupconsisting of straight or branched C₁-C₆ alkyl and straight or branchedC₁-C₆ alkoxy; and

wherein, each R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independentlyone or more substituents selected from the group consisting of hydrogen,halogen, straight or branched C₁-C₆ alkyl and straight or branched C₁-C₆alkoxy; R³, R⁵, R⁷ and R⁹ are independently hydrogen; straight orbranched C₁-C₆ alkyl or alkoxy; 3-8 membered heterocycloalkyl containingone or more heteroatoms selected from the group consisting of N and O;or —(C═O)NR²⁶R²⁷, wherein R²⁶ and R²⁷ are independently hydrogen,straight or branched C₁-C₃ alkyl or 3-8 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O substituted with 3-5 membered heterocycloalkyl containing one ormore oxygen atoms, or, R²⁶ and R²⁷ form 3-8 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O along with nitrogen atom to which they are attached, wherein,the alkyl or heterocycloalkyl is substituted with one or moresubstituents selected from the group consisting of —CN, halogen,straight or branched C₁-C₃ alkyl, and, 3-6 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O nonsubstituted or substituted with one or more straight orbranched C₁-C₃ alkyl R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ areindependently hydrogen or straight or branched C₁-C₃ alkyl, R¹², R¹³,R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently hydrogen or straightor branched C₁-C₃ alkyl, or, two of R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰and R²¹ bonded to the same carbon can form carbonyl along with thecarbon to which they are attached, and R¹⁶, R²² and R²⁵ areindependently hydrogen or straight or branched C₁-C₃ alkyl, wherein thealkyl can be substituted with one or more halogens).
 2. The methodaccording to claim 1, wherein: Z is —CN or methyl substituted with oneor more halogens; X is —NR^(a)— or —O—, wherein R^(a) is hydrogen orstraight or branched C₁-C₆ alkyl, wherein, the alkyl can be substitutedwith one or more substituents selected from the group consisting of —OHand C₁-C₃ alkoxy; R¹ is straight or branched C₁-C₆ alkyl, C₃-C₈cycloalkyl or C₆₋₁₀ aryl, wherein, the alkyl can be substituted with oneor more substituents selected from the group consisting of —OH, methyland methoxy, and the aryl can be substituted with one or moresubstituents selected from the group consisting of methyl and methoxy,nonsubstituted or substituted with one or more halogens; or, R^(a) canform nonsubstituted or substituted 5-6 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN, O and S along with R¹ and nitrogen atom to which they are attached,and the substituted heterocycloalkyl can be substituted with one or moresubstituents selected from the group consisting of straight or branchedC₁-C₃ alkyl and straight or branched C₁-C₃ alkoxy; and

wherein, R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independently one ormore substituents selected from the group consisting of hydrogen,halogen, straight or branched C₁-C₃ alkyl and straight or branched C₁-C₃alkoxy; R³, R⁵, R⁷ and R⁹ are independently hydrogen, straight orbranched C₁-C₃ alkyl or alkoxy, morpholinyl, piperazinyl, piperidinyl or—(C═O)NR²⁶R²⁷, wherein R²⁶ and R²⁷ are independently hydrogen, methyl,morpholinyl, piperazinyl or piperidinyl, or, R²⁶ and R²⁷ formmorpholinyl, piperazinyl or piperidinyl along with nitrogen atom towhich they are attached, wherein, the C₁-C₃ alkyl, morpholinyl,piperazinyl or piperidinyl can be substituted with one or moresubstituents selected from the group consisting of —CN, fluoro,oxetanyl, morpholinyl, piperazinyl, and, nonsubstituted or methylsubstituted piperidinyl, R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ areindependently hydrogen, methyl or ethyl, R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹,R²⁰ and R²¹ are independently hydrogen, methyl or ethyl, or, two of R²,R¹³, R¹⁴, R¹, R¹⁸, R¹⁹, R²⁰ and R²¹ bonded to the same carbon can formcarbonyl along with the carbon to which they are attached, and R¹⁶, R²²and R²⁵ are independently hydrogen, methyl nonsubstituted or substitutedwith one or more halogens or ethyl nonsubstituted or substituted withone or more halogens.
 3. The method according to claim 1, wherein: Z is—CN or —CF₃; X is —NR^(a)— or —O—, wherein R^(a) is hydrogen or methyl;R¹ is methyl, ethyl, n-propyl, isopropyl, cyclopropyl,

 1-methylcyclopropyl, or, phenyl substituted with one or more CF₃; or,R^(a) can form morpholinyl along with R¹ and nitrogen atom to which theyare attached; and

wherein, R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independently one ormore substituents selected from the group consisting of hydrogen,chloro, fluoro, methyl and methoxy; R³ and R⁷ are independently methoxy,

B⁵ and R⁹ are independently methyl, isopropyl

R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ are independently hydrogen ormethyl, R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independentlyhydrogen or methyl, or, two of R², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹bonded to the same carbon can form carbonyl along with the carbon towhich they are attached, and R¹⁶, R²² and R²⁵ are independentlyhydrogen, or, methyl nonsubstituted or substituted with one or morehalogens.
 4. The method according to claim 1, wherein: Z is —CN or —CF₃;X is —NR^(a)— or —O—, wherein R^(a) is hydrogen or methyl; R¹ is methyl,ethyl, n-propyl, isopropyl, cyclopropyl,

 1-methylcyclopropyl, or

or, R^(a) can form morpholinyl along with R¹ and nitrogen atom to whichthey are attached; and


5. The method according to claim 1, wherein the compound represented bychemical formula 1 is selected from the group consisting of thefollowing compounds: (1)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(2)4-(ethylamino)-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(3)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(4)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(5)4-((2-methoxyethyl)amino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(6)4-((2-methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(7)4-((2-methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(8)4-(ethylamino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(9)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(10)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(11)4-(propylamino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(12)6-((1-methyl-1H-pyrazol-4-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(13)6-((1-methyl-1H-pyrazol-3-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(14)4-(ethylamino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(15)4-(ethylamino)-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(16)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(17)6-((5-fluoro-2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(18)4-(ethylamino)-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(19)6-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(20)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(21)6-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(22)(R)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(23)(S)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(24)6-((4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-2-methoxyphenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(25)6-((4-(4,4-difluoropiperidine-1-carbonyl)-2-methoxyphenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(26)(R)-4-(ethylamino)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(27)(S)-4-(ethylamino)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(28)6-((4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-2-methoxyphenyl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(29)6-((4-(4,4-difluoropiperidine-1-carbonyl)-2-methoxyphenyl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(30)6-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(31)6-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(32)4-(ethylamino)-6-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(33)4-(ethylamino)-6-((1-isopropyl-5-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(34)6-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(35)6-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(36)6-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(37)6-((1-isopropyl-5-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(38)6-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(39)6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(40)4-(ethylamino)-6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(41)6-((5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(42)6-((5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(43)(R)-4-(ethylamino)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(44)(R)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(45)(5-methoxy-6-(4-(methylamino)-3-(trifluromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone;(46)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(47)4-methoxy-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(48)4-methoxy-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(49)4-ethoxy-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(50)4-ethoxy-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(51)(R)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-4-(1-methylcyclopropoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(52)6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-4-(1-methylcyclopropoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(53)N⁴-ethyl-3-(trifluoromethyl)-N⁶-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(54)N⁴-ethyl-N⁶-(1-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(55)N⁴-ethyl-N⁶-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(56)(4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(morpholino)methanone;(57)(4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(58)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone;(59)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-morpholinopiperidin-1-yl)methanone;(60)(2-fluoro-5-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(61)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(62)N⁶-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N⁴-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(63)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(64)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6yl)amino)phenyl)(morpholino)methanone;(65)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-morpholinopiperidin-1-yl)methanone;(66)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)-methanone;(67)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(68)N⁶-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(2-methoxyethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(69)N⁶-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N⁴-ethyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(70)(4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(71)4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-5methoxy-N-(1-(oxetanepiperidin-4-yl)benzamide;(72)4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzylamide;(73)2-fluoro-5-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)(1-methylpiperidin-4-yl)benzamide;(74)4-((4-(ethylamino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-N-(1-isopropylpiperidin-4-yl)-5-methoxybenzamide;(75)(R)-(2,4-dimethylpiperazin-1-yl)(2-fluoro-5-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)methanone;(76)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone;(77)N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6-amine;(78)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(79)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-methoxyethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(80)1-(6-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one;(81)N4-ethyl-N6-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(82)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(83)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(84)(3-methoxy-4-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenyl)(morpholino)methanone;(85)(3-methoxy-4-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenyl)(4-morpholinopiperidin-1-yl)methanone;(86)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)-N4-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(87)(3-methoxy-4-((4-methoxyethyl)(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone;(88)(3-methoxy-4-((4-methoxyethyl)(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)((4-morpholinopiperidin-1-yl)methanone;(89)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methoxyethyl)-N4-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(90)(4-(4-(isopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(91)(R)-(4-((4-((1-hydroxy-3-methylbutan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(92)(R)-(4-((4-((1-hydroxy-3-methylbutan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]amino)-3-methoxyphenyl)(morpholino)methanone;(93)(S)-(4-((4-(2-butylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)-methanone;(94)(4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(95)(4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(morpholino)methanone;(96)5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-methoxy-2-methylisoindolin-1-one;(97)7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[1,4]oxazin-3(4H)-1-one;(98)6-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-5-methoxy-2-methylisoindolin-1-one;(99)4-(ethylamino)-6-((6-methoxy-2-methyl-3-oxoisoindol-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(100)6-((2(2-cyanopropan-2-yl)-4-methylthiazol-5-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(101)(6-chloro-5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-methylisoindolin-1-one;(102)5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-methylisoindolin-1-one;(103)4-(ethylamino)-6-((2-methyl-1-oxoisoindol-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(104)6-((6-chloro-2-methyl-1-oxoisoindolin-5-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;and, (105)4-(ethylamino)-6-((6-methoxy-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.6. (canceled)
 7. A pharmaceutical composition comprising a compoundrepresented by chemical formula 1:

the optical isomer thereof or a pharmaceutically acceptable saltthereof, wherein: Z is cyano (—CN): or straight or branched C₁-C₃ alkylsubstituted with one or more halogens: X is —NR^(a)—, —O— or —S—,wherein R^(a) is hydrogen or straight or branched C₁-C₁₀ alkyl, wherein,the alkyl can be substituted with one or more substituents selected fromthe group consisting of —OH and C₁-C₃ alkoxy; R¹ is straight or branchedC₁-C₁₀ alkyl, C₃-C₈ cycloalkyl or C₆₋₁₄ aryl, wherein, the alkyl orcycloalkyl can be substituted with one or more substituents selectedfrom the group consisting of —OH, and, straight or branched C₁-C₃ alkyland C₁-C₃ alkoxy, and the aryl can be substituted with one or moresubstituents selected from the group consisting of straight or branchedC₁-C₃alkyl and straight or branched C₁-C₃ alkoxy, nonsubstituted orsubstituted with one or more halogens; or, R^(a) can form nonsubstitutedor substituted 5-8 membered heterocycloalkyl containing one or moreheteroatoms selected from the group consisting of N, O and S along withR¹ and nitrogen atom to which they are attached, and the substitutedheterocycloalkyl can be substituted with one or more substituentsselected from the group consisting of straight or branched C₁-C₆ alkyland straight or branched C₁-C₆ alkoxy; and

wherein, each R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independentlyone or more substituents selected from the group consisting of hydrogen,halogen, straight or branched C₁-C₆ alkyl and straight or branched C₁-C₆alkoxy; R³, R⁵, R⁷ and R⁹ are independently hydrogen; straight orbranched C₁-C₆ alkyl or alkoxy; 3-8 membered heterocycloalkyl containingone or more heteroatoms selected from the group consisting of N and O;or —(C═O)NR²⁶R²⁷, wherein R²⁶ and R²⁷ are independently hydrogen,straight or branched C₁-C₃ alkyl or 3-8 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O substituted with 3-5 membered heterocycloalkyl containing one ormore oxygen atoms, or, R²⁶ and R²⁷ form 3-8 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O along with nitrogen atom to which they are attached, wherein,the alkyl or heterocycloalkyl is substituted with one or moresubstituents selected from the group consisting of —CN, halogen,straight or branched C₁-C₃ alkyl, and, 3-6 membered heterocycloalkylcontaining one or more heteroatoms selected from the group consisting ofN and O nonsubstituted or substituted with one or more straight orbranched C₁-C₃ alkyl R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ areindependently hydrogen or straight or branched C₁-C₃ alkyl, R¹², R¹³,R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independently hydrogen or straightor branched C₁-C₃ alkyl, or, two of R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰and R²¹ bonded to the same carbon can form carbonyl along with thecarbon to which they are attached, and R¹⁶, R²² and R²⁵ areindependently hydrogen or straight or branched C₁-C₃ alkyl, wherein thealkyl can be substituted with one or more halogens.
 8. Thepharmaceutical composition according to claim 7, wherein the compositionfurther comprises diluents or excipients. 9-12. (canceled)
 13. Themethod according to claim 1, wherein the cancer is brain cancer, braintumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma,meningioma, brain lymphoma, oligodendroglioma, intracranial carcinoma,ependymoma, brainstem tumor, polymorphic glioblastoma, malignant glioma,brain blastoma, metastatic brain tumor, head and neck tumor, larynxcancer, oropharyngeal cancer, nasal cavity/paranasal sinus cancer,nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer,thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer,non-small cell lung cancer, thymus cancer, mediastinal tumor, esophagealcancer, breast cancer, male breast cancer, abdominal tumor, stomachcancer, liver cancer, gallbladder cancer, biliary cancer, pancreaticcancer, small bowel cancer, colon cancer, rectal cancer, anal cancer,bladder cancer, kidney cancer, male genital tumor, penile cancer,prostate cancer, female genital tumor, cervical cancer, endometrialcancer, ovarian cancer, uterine sarcoma, vaginal cancer, female externalgenital cell cancer, female urethral cancer or skin cancer.
 14. Themethod according to claim 1, wherein the cancer is brain cancer,non-small cell lung cancer, breast cancer, colon cancer, rectal cancer,kidney cancer, pancreatic cancer, ovarian cancer, salivary gland cancer,or prostate cancer.
 15. The method according to claim 1, wherein themetabolic disease is diabetes, hypoglycemia, hypercholesterolemia,hyperlipidemia, hemochromatosis, amyloidosis or porphyria.
 16. Thepharmaceutical composition according to claim 7, wherein: Z is —CN ormethyl substituted with one or more halogens; X is —NR^(a)— or —O—,wherein R^(a) is hydrogen or straight or branched C₁-C₆ alkyl, wherein,the alkyl can be substituted with one or more substituents selected fromthe group consisting of —OH and C₁-C₃ alkoxy; R¹ is straight or branchedC₁-C₆ alkyl, C₃-C₈ cycloalkyl or C₆₋₁₀ aryl, wherein, the alkyl can besubstituted with one or more substituents selected from the groupconsisting of —OH, methyl and methoxy, and the aryl can be substitutedwith one or more substituents selected from the group consisting ofmethyl and methoxy, nonsubstituted or substituted with one or morehalogens; or, R^(a) can form nonsubstituted or substituted 5-6 memberedheterocycloalkyl containing one or more heteroatoms selected from thegroup consisting of N, O and S along with R¹ and nitrogen atom to whichthey are attached, and the substituted heterocycloalkyl can besubstituted with one or more substituents selected from the groupconsisting of straight or branched C₁-C₃ alkyl and straight or branchedC₁-C₃ alkoxy; and

wherein, R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independently one ormore substituents selected from the group consisting of hydrogen,halogen, straight or branched C₁-C₃ alkyl and straight or branched C₁-C₃alkoxy; R³, R⁸, R⁷ and R⁹ are independently hydrogen, straight orbranched C₁-C₃ alkyl or alkoxy, morpholinyl, piperazinyl, piperidinyl or—(C═O)NR²⁶R²⁷, wherein R²⁶ and R²⁷ are independently hydrogen, methyl,morpholinyl, piperazinyl or piperidinyl, or, R²⁶ and R²⁷ formmorpholinyl, piperazinyl or piperidinyl along with nitrogen atom towhich they are attached, wherein, the C₁-C₃ alkyl, morpholinyl,piperazinyl or piperidinyl can be substituted with one or moresubstituents selected from the group consisting of —CN, fluoro,oxetanyl, morpholinyl, piperazinyl, and, nonsubstituted or methylsubstituted piperidinyl, R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ areindependently hydrogen, methyl or ethyl, R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹,R²⁰ and R²¹ are independently hydrogen, methyl or ethyl, or, two of R²,R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ bonded to the same carbon can formcarbonyl along with the carbon to which they are attached, and R¹⁶, R²²and R²⁵ are independently hydrogen, methyl nonsubstituted or substitutedwith one or more halogens or ethyl nonsubstituted or substituted withone or more halogens.
 17. The pharmaceutical composition according toclaim 7, wherein: Z is —CN or —CF₃; X is —NR^(a)— or —O—, wherein R^(a)is hydrogen or methyl; R¹ is methyl, ethyl, n-propyl, isopropyl,cyclopropyl,

 1-methylcyclopropyl, or, phenyl substituted with one or more CF₃; or,R^(a) can form morpholinyl along with R¹ and nitrogen atom to which theyare attached; and

wherein, R², R⁴, R⁶, R⁸, R¹¹, R¹⁷, R²³ and R²⁴ are independently one ormore substituents selected from the group consisting of hydrogen,chloro, fluoro, methyl and methoxy; R³ and R⁷ are independently methoxy,

R⁵ and R⁹ are independently methyl, isopropyl, N or

R¹⁰ is —CR²⁸R²⁹—CN, wherein R²⁸ and R²⁹ are independently hydrogen ormethyl, R¹², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹ are independentlyhydrogen or methyl, or, two of R², R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰ and R²¹bonded to the same carbon can form carbonyl along with the carbon towhich they are attached, and R¹⁶, R²² and R²⁵ are independentlyhydrogen, or, methyl nonsubstituted or substituted with one or morehalogens.
 18. The pharmaceutical composition according to claim 7,wherein: Z is —CN or —CF₃; X is —NR^(a)— or —O—, wherein R^(a) ishydrogen or methyl; R¹ is methyl, ethyl, n-propyl, isopropyl,cyclopropyl,

 1-methylcyclopropyl, or

or, R^(a) can form morpholinyl along with R¹ and nitrogen atom to whichthey are attached; and


19. The pharmaceutical composition according to claim 7, wherein thecompound represented by chemical formula 1 is selected from the groupconsisting of the following compounds: (1)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(2)4-(ethylamino)-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(3)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(4)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(5)4-((2-methoxyethyl)amino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(6)4-((2-methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(7)4-((2-methoxyethyl)amino)-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(8)4-(ethylamino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(9)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(10)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(11)4-(propylamino)-6-((3,4,5-trimethoxyphenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(12)6-((1-methyl-1H-pyrazol-4-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(13)6-((1-methyl-1H-pyrazol-3-yl)amino)-4-(propylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(14)4-(ethylamino)-6-((1-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(15)4-(ethylamino)-6-((1-methyl-1H-pyrazol-3-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(16)6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(17)6-((5-fluoro-2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(18)4-(ethylamino)-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(19)6-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(20)6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(21)6-((5-fluoro-2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-4-((2-methoxyethyl)(methyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(22)(R)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(23)(S)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(24)6-((4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-2-methoxyphenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(25)6-((4-(4,4-difluoropiperidine-1-carbonyl)-2-methoxyphenyl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(26)(R)-4-(ethylamino)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(27)(S)-4-(ethylamino)-6-((2-methoxy-4-(2-methylmorpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(28)6-((4-((2R,6S)-2,6-dimethylmorpholine-4-carbonyl)-2-methoxyphenyl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(29)6-((4-(4,4-difluoropiperidine-1-carbonyl)-2-methoxyphenyl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(30)6-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(31)6-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(32)4-(ethylamino)-6-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(33)4-(ethylamino)-6-((1-isopropyl-5-methyl-1H-pyrazol-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(34)6-((1,5-dimethyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(35)6-((1,3-dimethyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(36)6-((1-isopropyl-3-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(37)6-((1-isopropyl-5-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(38)6-((1-(2-cyanopropan-2-yl)-3-methyl-1H-pyrazol-4-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(39)6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(40)4-(ethylamino)-6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(41)6-((5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(42)6-((5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(43)(R)-4-(ethylamino)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(44)(R)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-4-(methylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(45)(5-methoxy-6-(4-(methylamino)-3-(trifluromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone;(46)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(47)4-methoxy-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(48)4-methoxy-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(49)4-ethoxy-6-((2-methoxy-4-(4-morpholinopiperidine-1-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(50)4-ethoxy-6-((2-methoxy-4-(morpholine-4-carbonyl)phenyl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(51)(R)-6-((3-methoxy-5-(2-methylmorpholine-4-carbonyl)pyridin-2-yl)amino)-4-(1-methylcyclopropoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(52)6-((3-methoxy-5-(morpholine-4-carbonyl)pyridin-2-yl)amino)-4-(1-methylcyclopropoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(53)N⁴-ethyl-3-(trifluoromethyl)-N⁶-(3,4,5-trimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(54)N⁴-ethyl-N⁶-(1-methyl-1H-pyrazol-3-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(55)N⁴-ethyl-N⁶-(1-methyl-1H-pyrazol-4-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(56)(4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(morpholino)methanone;(57)(4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(58)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone;(59)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-morpholinopiperidin-1-yl)methanone;(60)(2-fluoro-5-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(61)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(62)N⁶-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N⁴-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(63)(3-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(64)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6yl)amino)phenyl)(morpholino)methanone;(65)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-morpholinopiperidin-1-yl)methanone;(66)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)-methanone;(67)(3-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(68)N⁶-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(2-methoxyethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(69)N⁶-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N⁴-ethyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(70)(4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(71)4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-5methoxy-N-(1-(oxetanepiperidin-4-yl)benzamide;(72)4-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzylamide;(73)2-fluoro-5-methoxy-4-((4-((2-methoxyethyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)(1-methylpiperidin-4-yl)benzamide;(74)4-((4-(ethylamino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-fluoro-N-(1-isopropylpiperidin-4-yl)-5-methoxybenzamide;(75)(R)-(2,4-dimethylpiperazin-1-yl)(2-fluoro-5-methoxy-4-((4-(methylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)methanone;(76)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone;(77)N-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-6-amine;(78)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(79)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-methoxyethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(80)1-(6-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one;(81)N4-ethyl-N6-(7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(82)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(83)(3-methoxy-4-((4-morpholino-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(4-(4-methylpiperazin-1-yl)piperidin-1-yl)methanone;(84)(3-methoxy-4-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenyl)(morpholino)methanone;(85)(3-methoxy-4-(3-(trifluoromethyl)-4-(3-(trifluoromethyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenyl)(4-morpholinopiperidin-1-yl)methanone;(86)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-3-(trifluoromethyl)-N4-(3-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(87)(3-methoxy-4-((4-methoxyethyl)(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)(morpholino)methanone;(88)(3-methoxy-4-((4-methoxyethyl)(methyl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)phenyl)((4-morpholinopiperidin-1-yl)methanone;(89)N6-(5-chloro-1-((3S,4S)-3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)methoxyethyl)-N4-methyl-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-4,6-diamine;(90)(4-(4-(isopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(91)(R)-(4-((4-((1-hydroxy-3-methylbutan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(92)(R)-(4-((4-((1-hydroxy-3-methylbutan-2-yl)amino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]amino)-3-methoxyphenyl)(morpholino)methanone;(93)(S)-(4-((4-(2-butylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)-methanone;(94)(4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methoxyphenyl)(4-morpholinopiperidin-1-yl)methanone;(95)(4-((4-(cyclopropylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-3-methoxyphenyl)(morpholino)methanone;(96)5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-methoxy-2-methylisoindolin-1-one;(97)7-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-6-methoxy-2,2,4-trimethyl-2H-benzo[1,4]oxazin-3(4H)-1-one;(98)6-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-5-methoxy-2-methylisoindolin-1-one;(99)4-(ethylamino)-6-((6-methoxy-2-methyl-3-oxoisoindol-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(100)6-((2(2-cyanopropan-2-yl)-4-methylthiazol-5-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(101)(6-chloro-5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-methylisoindolin-1-one;(102)5-((4-(ethylamino)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)amino)-2-methylisoindolin-1-one;(103)4-(ethylamino)-6-((2-methyl-1-oxoisoindol-5-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;(104)6-((6-chloro-2-methyl-1-oxoisoindolin-5-yl)amino)-4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile;and, (105)4-(ethylamino)-6-((6-methoxy-2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)amino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile.